Therapeutic Drug Monitoring最新文献

Background: The endocannabinoid system regulates immune function, inflammation, and metabolism and has gained increasing attention in clinical research. However, the instability, low abundance, and physicochemical complexity of endocannabinoids (ECs) and EC-like substances (EC-like) make their quantification in plasma analytically challenging.

Objective and methods: The authors developed and validated a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of N-arachidonoylethanolamide (AEA), 2-arachidonoylglycerol, and its isomer 1-arachidonoylglycerol (2-AG/1-AG), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA) in human plasma.

Results: Extraction was performed using liquid-liquid extraction combined with liquid chromatography-tandem mass spectrometry. The method achieved lower limits of quantification of 0.1 mcg/L for AEA, 0.2 mcg/L for 2-AG/1-AG, and 0.5 mcg/L for OEA and PEA, with calibration curves showing high linearity (R2 ≥ 0.995). Intra-assay and interassay accuracy and precision were both within 15%. Additional validation parameters, including selectivity, recovery, carryover, matrix suitability, and dilution integrity, fulfilled regulatory criteria. Preanalytical handling significantly influenced concentrations: Delayed centrifugation and postthaw storage increased AEA, OEA, and PEA levels. The validated method was applied to plasma samples from patients coinfected with HIV and hepatitis C virus, enabling reproducible quantification of ECs and EC-like substances in a clinically relevant cohort.

Conclusions: The study demonstrates that biological and technical factors markedly affect plasma EC and EC-like concentrations. Standardized preanalytical processing is therefore essential for accurate measurement, and the proposed method provides a robust tool for clinical and pharmacological research.

Abstract: Omadacycline is a novel aminomethylcycline antibiotic that retains its antibacterial activity against strain-specific efflux pumps and ribosomal protective protein mechanisms of tetracycline resistance. To determine the concentration of omadacycline in human plasma, an ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed to provide a basis for therapeutic monitoring of omadacycline in clinical settings. The experimental approach involves using an ACQUITY UPLC BEH C18 column (2.1 × 50 mm, 1.7 μm), with a mobile phase of 0.1% aqueous formic acid:acetonitrile (90:10, vol/vol), a flow rate of 0.3 mL·min -1 , a column temperature of 40°C, and an injection volume of 0.1 μL. Protein precipitation was employed as pretreatment, using acetonitrile as the precipitant. Minocycline was used as an internal standard. Omadacycline and internal standard were monitored in positive ion mode with the following mass transition pairs: mass/charge (m/z) = 557.1→ 470.1 for omadacycline, and m/z = 458.3→ 440.9 for IS, respectively. The established method showed a good linearity in the range of 0.01-10 mcg/mL of omadacycline (Y = 0.4603X + 0.0452, r 2 = 0.999), with the lower limit of quantification of 0.01 mcg/mL. Method validation included accuracy, precision, matrix effect, recovery, carryover, dilution integrity, and stability, all of which met the requirements of the US Food and Drug Administration for the validation of bioanalytical methods. This method has been successfully applied to therapeutic drug monitoring in patients.

Background: Previous research has shown that a plasma lamotrigine concentration of 12.7 µmol/L may be a threshold for a good therapeutic response to lamotrigine augmentation therapy in Japanese patients with treatment-resistant depression. The optimal dose of lamotrigine can be predicted using a previously established nomogram based on the plasma lamotrigine concentration at week 2. The aim of the present study was to prospectively evaluate the validity of this nomogram.

Methods: Participants included 59 patients with depression who showed insufficient therapeutic responses to psychotropics, including antidepressants, antipsychotics, and mood stabilizers. The patients were diagnosed with major depressive disorder (n = 26), bipolar II disorder (n = 25), or bipolar I disorder (n = 8). Lamotrigine was administered to all the patients. The initial dose of lamotrigine was 25 mg/d for 32 patients not taking valproate and 25 mg/d every other day for 27 patients taking valproate. Blood samples were collected at week 2 and at least 2 weeks after the final daily dose, which was estimated by a nomogram based on the plasma lamotrigine concentration at week 2. The plasma concentrations of lamotrigine were measured by liquid chromatography-mass spectrometry.

Results: In 30 of the 32 patients (93.8%) who were not taking valproate and 23 of the 27 patients (85.2%) who were taking valproate, a plasma lamotrigine concentration of 12.7 mcg/mL or higher was achieved at the final daily administration of lamotrigine.

Conclusions: The results of the present study suggest that the previously established nomogram is valid for determining the optimal dose of lamotrigine for Japanese patients with treatment-resistant depression in clinical settings.

Background: Therapeutic drug monitoring optimizes oral anticancer drug treatment by measuring plasma levels. Volumetric absorptive microsampling (VAMS) allows home sampling with a minimal blood sample. However, methods for converting whole blood into plasma are required to interpret these results. This study aimed to establish conversion methods for abiraterone, alectinib, cabozantinib, imatinib, olaparib, sunitinib, and their metabolites, while assessing the differences between venous and capillary blood. The feasibility of home sampling was also evaluated.

Methods: Plasma and VAMS samples, both from venipuncture-collected whole blood tubes and from a finger prick, were collected from each patient. The VAMS samples were deemed comparable if their concentrations were within ±20% of each other for ≥2/3rd of the patients. The Passing-Bablok regression and conversion factor methods were tested for the plasma and VAMS finger prick samples. The estimated plasma concentrations using both methods were required to be within ±20% of the measured plasma concentrations for ≥2/3rd of the pairs.

Results: Overall, 153 patients were enrolled in this study. Conversion methods were applied to the VAMS samples, and the acceptance criteria were met for alectinib-M4, cabozantinib, imatinib, N-desmethyl imatinib, olaparib, sunitinib, and N-desethyl sunitinib but not for abiraterone, D4A, or alectinib. The capillary and venous VAMS concentrations were similar, except for that of D4A. Patients were positive toward home sampling.

Conclusions: The established VAMS conversion methods for 7 out of 10 oral targeted anticancer drugs or metabolites met the acceptance criteria. Future studies need to validate the conversion methods with an independent cohort and integrate home sampling via VAMS to provide patients with an alternative to venipuncture at the outpatient clinic.

Background: Therapeutic drug monitoring of immunosuppressants is critical in balancing insufficient immunosuppression due to underdosing, and severe adverse effects due to overdosage. For a more comprehensive therapeutic drug monitoring and follow-up of transplant patients, the aim was to develop a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of tacrolimus, cyclosporine A, tryptophan, kynurenine, and creatinine using a volumetric absorptive microsampling device.

Methods: Venous and capillary blood samples were simultaneously collected using a volumetric absorptive microsampling device called Mitra. The method involved protein precipitation followed by offline solid-phase extraction using a positive pressure manifold. Chromatographic separation was achieved by a formic acid-ammonium formate-methanol gradient on a Synergi Polar reversed-phase column. Multiple reaction monitoring in the positive ion mode and stable isotope-labeled internal standards were used for quantification. Validation was performed according to the European Medicines Agency and US Food and Drug Administration (FDA) guidelines.

Results: Validation was successful, meeting European Medicines Agency and FDA guidelines. Investigation of selectivity, accuracy, and precision met the required criteria of a deviation <15%. Internal standards successfully compensated potential matrix effects. A comparison of 26 anonymized samples from transplant patients on Mitra with venous blood controls demonstrated the method's suitability.

Conclusions: For the first time, we herein describe a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of tacrolimus, cyclosporine A, tryptophan, kynurenine, and creatinine on Mitra. Self-collection of samples may facilitate therapeutic monitoring. Simultaneous determination of creatinine may help monitor kidney function, while tryptophan and kynurenine may serve as a biomarker for early detection of transplant rejection.

Background: Patients with inflammatory bowel disease (IBD) to be treated with thiopurines should undergo preemptive genotyping for reduced-function thiopurine methyltransferase ( TPMT ) polymorphisms. Therapeutic drug monitoring (TDM) is recommended in cases of toxicity or a lack of efficacy. The relationship between TPMT genotype and 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) concentrations in the early steady state was assessed.

Methods: Consecutive adults with IBD to be treated with azathioprine underwent preemptive TPMT genotyping and were dosed accordingly. All patients underwent TDM after 4-6 weeks of treatment and occasionally thereafter.

Results: Of the 235 included patients, 45 were not genotyped for various reasons (45 samples at first TDM, 66 overall). Of the 190 patients who were genotyped, 19 (10%) were heterozygous (*1/*3) (19 samples at first TDM, 32 overall) and 171 (90%) were wild-type (171 samples at first TDM, 280 overall). At first TDM, 7 patients were hypermethylators, and 6 were identified at later TDMs. Compared with patients with a wild-type genotype or those who were not genotyped, those who were heterozygous consistently had markedly higher 6-TGN (2-fold, 3.7-fold if dose-adjusted) and lower 6-MMP (75%-90%, 30%-50% if dose-adjusted) concentrations (pmol/8 × 10 8 red blood cells). Based on the 6-TGN/6-MMP profiles, they were 2-3 times less likely to be classified as receiving "too low of a dose" (6-TGN <235 and 6-MMP <5700 pmol/8 × 10 8 red blood cells), and 4-20 times more likely to be classified as receiving "too high of a dose" (6-TGN >450).

Conclusions: These data support the importance of TPMT genotyping and suggest that thiopurine TDM generates supplementary information and should be performed for all patients.

Background: Perampanel is a promising epilepsy treatment with an innovative mechanism of action. This study was performed to investigate the factors affecting perampanel clearance in a population pharmacokinetic (PPK) model of Chinese pediatric and adult patients with epilepsy.

Methods: A total of 135 perampanel plasma concentrations from 125 patients with epilepsy were analyzed using the PPK model with nonlinear mixed-effects modeling. One-compartment and proportional residual models best described the pharmacokinetics of perampanel. Covariate effects on the model parameters were assessed using forward and backward elimination. Goodness-of-fit, bootstrapping, visual predictive checks, and normalized prediction distribution errors were used to evaluate the model. Monte Carlo simulations were conducted to assess the impact of covariate combinations on perampanel plasma concentrations at different dosages.

Results: In the final PPK model, body weight (BW), concomitant carbamazepine (CBZ), oxcarbazepine (OXC), and C-reactive protein (CRP) levels significantly influenced perampanel clearance. The interindividual clearance was calculated as follows: 0.84 × (BW/70) 0.53 × e CBZ × e OXC × e CRP (CBZ = 0.98, when comedicated with carbamazepine; OXC = 0.43, when comedicated with oxcarbazepine; CRP = -0.69, when CRP >15 mg/L, otherwise = 0). The estimates (relative standard error) for clearance and apparent volume of distribution of the final model were 0.84 L/h (8.75%) and 64.35 L (19.78%), respectively. The model maintained its stability and effectiveness with moderate predictability.

Conclusions: BW and CBZ, OXC, and CRP levels may influence perampanel clearance in both pediatric and adult patients with epilepsy according to a population pharmacokinetic model that included real-world data.

Background: Abiraterone, an active metabolite of abiraterone acetate, is used for the treatment of prostate cancer. Therapeutic drug monitoring (TDM) of abiraterone could improve treatment outcomes. However, its stability in plasma for only 4 hours at room temperature, is making the TDM implementation difficult in clinical practice. Stabilization experiments were performed in our laboratory using esterase inhibitors for the stabilization of abiraterone acetate in preclinical samples. The esterase inhibitor bis(4-nitrophenyl) phosphate (BNPP) stabilizes abiraterone acetate and abiraterone as well. Therefore, we investigated whether the esterase inhibitor BNPP could stabilize abiraterone in fresh human plasma.

Methods: BNPP at 1 and 10 mM were evaluated for its stabilizing effects on abiraterone in fresh human K 2 EDTA plasma. The samples were analyzed using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method. A partial validation assessed BNPP's impact on accuracy, precision, selectivity, and specificity within the fully validated LC-MS/MS method.

Results: BNPP at 10 mM, but not 1 mM, effectively prevented abiraterone degradation in fresh human K 2 EDTA plasma, maintaining stability for at least 5 days at room temperature. Partial validation confirmed that all results met the acceptance criteria of the European Medicines Agency guidelines and the US Food and Drug Administration guidance.

Conclusions: We demonstrated that the esterase inhibitor BNPP effectively stabilizes abiraterone in fresh human K 2 EDTA plasma. BNPP had no significant effect on the accuracy, precision, selectivity, or specificity of LC-MS/MS for abiraterone detection. The addition of BNPP to clinical abiraterone samples may be helpful in implementing abiraterone TDM in daily clinical practice.

Background: Nirmatrelvir/ritonavir is licensed for the treatment of mild-to-moderate coronavirus disease (COVID-19) in patients at an increased risk of progression to severe disease. However, data on the real-world plasma exposure to nirmatrelvir/ritonavir remain limited, particularly in Chinese patients. This study aimed to assess the nirmatrelvir/ritonavir trough concentration (C trough ) and identify its critical factors in hospitalized Chinese patients treated with nirmatrelvir/ritonavir 300 mg/100 mg twice daily over a 5-day course.

Methods: A high-performance liquid chromatography-tandem mass spectrometry assay was developed and validated to measure the nirmatrelvir/ritonavir C trough . Correlation analyses were performed to identify the variables influencing nirmatrelvir/ritonavir C trough .

Results: Among the 110 patients, 100% had plasma concentrations above the antiviral in vitro 90% effective concentration. The median C trough of nirmatrelvir was 4.55 mcg/mL (15.6× 90% effective concentration), ranging from 0.65 to 12.44 mcg/mL. Nirmatrelvir C trough in normal and mild renal impairment cohorts were comparable (4.09 ± 1.97 mcg/mL and 4.57 ± 2.21 mcg/mL) but significantly increased in the moderate renal impairment cohort (6.41 ± 2.31 mcg/mL). Sex, age, and obesity were not significantly associated with nirmatrelvir exposure.

Conclusions: Nirmatrelvir C trough was high in Chinese patients with COVID-19, and therapeutic drug monitoring should not be routinely recommended, except in patients with renal impairment.