Trough Plasma Research Articles

Amikacin therapeutic drug monitoring: Evaluation of therapy performance and analytical techniques in a developing country setting.

Healthcare systems face several challenges, with microbial infections being one of the main concerns. Therapeutic drug monitoring (TDM) is a strategy that has been encouraged to optimize antimicrobial regimens, particularly those with significant toxicity and narrow therapeutic indices, such as amikacin (AMK). We aimed to evaluate AMK concentrations of patients in a non-routine TDM setting and compare the performance of immunoassay and chromatography methods for routine clinical use. In this prospective study, peak (Cmax) and trough (Cmin) plasma samples were collected from 39 adult patients and quantified by ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS/MS). Relevant clinical information was collected from medical records. AMK concentrations and clinical data were analyzed to evaluate therapy performance and influencing factors. In addition, fluorescence polarized immunoassay (FPIA) and UPLC-MS/MS were compared with Passing-Bablok regression and Bland-Altman plot analysis. AMK concentrations varied widely, with a median Cmax of 41.40µg/mL (interquartile range [IQR] 27.60 - 56.75µg/mL) and a median Cmin of 1.87µg/mL (IQR 0.7 - 6.19µg/mL). A high proportion of patients (83.1%) failed to achieve the Cmax therapeutic target, while 31.7% failed to achieve the Cmin therapeutic target. Overall, elderly patients and those with reduced renal function had higher Cmax target attainment, while the same groups had lower Cmin target attainment. The method comparison showed a mean difference of 1.54% (limits of agreement -42.46% to 45.54%) in measured concentrations, with good correlation and no constant or proportional differences. Many patients failed to reach the Cmax target and were at risk of treatment failure, although adequate Cmin was achieved more often. TDM with dose adjustments could improve AMK therapy, but further research is needed.

Influence of CYP2C8*3 and ABCG2 C421A genetic polymorphisms on trough concentration and molecular response of imatinib in Egyptian patients with chronic myeloid leukemia.

The treatment landscape for chronic myeloid leukemia (CML) has been revolutionized by the introduction of imatinib, a tyrosine kinase inhibitor, which has transformed the disease from a fatal condition into a manageable chronic illness for a substantial number of patients. Despite this, some individuals do not respond adequately to the treatment, and others may experience disease progression even with continued therapy. This study examined how CYP2C8*3 (G416A; rs11572080) and ABCG2 C421A (rs2231142) single nucleotide polymorphisms (SNPs) affect the plasma trough concentration and therapeutic response of imatinib in Egyptian CML patients. The study included fifty patients with chronic-phase CML, who were categorized into two groups: responders (n = 26) and non-responders (n = 24), according to their BCR-ABL1 transcription levels after 12 months of imatinib treatment. Genotyping of the CYP2C8*3 and ABCG2 C421A polymorphisms was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), while plasma trough concentrations were determined through high-performance liquid chromatography with ultraviolet-diode array detection (HPLC-UV/DAD). Patients with the CA genotype of ABCG2 C421A showed significantly higher mean plasma trough concentrations of imatinib (CA: 1731 ± 424.7 ng/mL; CC: 1294 ± 381.3 ng/mL; p = 0.0132) and demonstrated a better molecular response compared to those with the CC genotype (p = 0.0395). The ABCG2 C421A polymorphism significantly influenced imatinib plasma trough concentrations and molecular responses in Egyptian chronic-phase CML patients. Genotyping of this polymorphism in these patients could assist in optimizing imatinib therapy, predicting more favorable treatment outcomes, and enabling the development of more personalized treatment plans.

Effects of CYP3A5 polymorphism and renal impairment on the drug interaction between venetoclax and fluconazole in acute myeloid leukaemia patients

The aim of this study was to investigate the effects of renal function and CYP3A5 polymorphism on the drug interaction between venetoclax and fluconazole in thirty acute myeloid leukaemia patients. The area under the plasma concentration-time curve (AUC) and trough concentration (C0) of venetoclax and the fluconazole C0 were obtained from plasma samples on day 7 later after initiation of venetoclax 200 mg/day combined with fluconazole. The fluconazole C0 values in patients with moderate and severe renal impairment were significantly higher than those in patients with normal or mild impairment (median values 7037, 6234, and 4813 ng/mL, respectively, P = 0.026). In patients with CYP3A5*3/*3 genotype, the AUC0-24 and C0 of venetoclax were not associated with fluconazole C0; however, in patients with a CYP3A5*1 allele, a significant positive correlation was observed between venetoclax C0 and fluconazole C0 (r = 0.782, P = 0.004). The metabolism of venetoclax by CYP3A4 is inhibited even at low fluconazole C0. In patients with a CYP3A5*1 allele, CYP3A5 is inhibited when high fluconazole C0 is induced by renal impairment. The dose of fluconazole for prophylaxis may be 100 mg in patients with severe renal impairment receiving venetoclax therapy.

Predictive factors for first dose reduction and interruption of lenvatinib after beginning of the standard dose in Japanese patients with thyroid cancer.

The associations between first dose reduction or interruption by side effects and lenvatinib plasma trough concentration (C0) after administration of a starting dose of 24 mg in 70 Japanese patients with thyroid cancer were evaluated. Plasma samples were collected each week for 1 month and at the first incidence of side effects leading to dose reduction or interruption after beginning administration of 24 mg lenvatinib. The area under the receiver operating characteristic curve was 0.789 at a lenvatinib C0 threshold of 128.25 ng/mL for predicting the first dose reduction or interruption. The median time to the first dose reduction or interruption was 14.0 days in patients with a C0 of≥128.25 ng/mL and 21.0 days in those with a C0 of<128.25 ng/mL (P = 0.001). At one, two, three and four weeks respectively, the first dose reduction or interruption was associated with body weight (P = 0.034); sex (P = 0.021); sex, age, and lenvatinib C0 of≥ 128.25 ng/mL (P = 0.025, 0.024, and 0.048, respectively); and age and lenvatinib C0 of ≥ 128.25 ng/mL (each P = 0.004). On day 8 after administration of 24mg lenvatinib, lenvatinib dose may be adjusted based on the target C0 of 128.25 ng/mL to maintain a high dose intensity during this early phase; however, because persistence of a higher C0 of 128.25 ng/mL causes early dose interruption or reduction, prospective dose reduction based on the next lower target C0 for the maintenance phase may be necessary.

Therapeutic Drug Monitoring of Nirmatrelvir/Ritonavir (Paxlovid) in Patients Treated for COVID-19: Results from a Prospective Multicenter Observational Study

Background: Paxlovid is a combination of the antiviral agents nirmatrelvir and ritonavir indicated for the oral treatment of high-risk, symptomatic patients with coronavirus disease 2019 (COVID-19). As real-world data on the plasma concentrations of nirmatrelvir/ritonavir (Paxlovid) are limited, the aim of this study was to investigate nirmatrelvir/ritonavir plasma trough levels in a clinical setting using therapeutic drug monitoring. Methods: A prospective, noninterventional, multicenter, observational clinical study was conducted in which the plasma trough levels of nirmatrelvir/ritonavir were simultaneously determined by using liquid chromatography tandem mass spectrometry in patients with symptomatic COVID-19. The blood samples were collected on days 1, 3, and 5 after the first full-dose day (day 0), and patient data such as sex, height, weight, renal function, liver enzymes, and concomitant (co-) medications were obtained to describe the plasma levels with respect to potential influencing factors. Results: A total of 46 blood samples from 21 patients were analyzed. The geometric mean Cmin was 4997 ng/mL for nirmatrelvir and 529.4 ng/mL for ritonavir. The plasma concentrations covered a wide range, the highest being observed in patients with advanced age and renally excreted comedications. Patients older than 65 years had a significantly higher risk of achieving excessive plasma trough concentrations above 8840 ng/mL for nirmatrelvir and 1440 ng/mL for ritonavir compared with younger patients (odds ratio 11.2, 95% confidence interval 1.04–120.4). Conclusions: The plasma trough concentrations of nirmatrelvir and ritonavir in patients treated for symptomatic COVID-19 were higher than the reference values of 2210 ng/mL for nirmatrelvir and 360 ng/mL for ritonavir stated in the product characteristics. Advanced age and renally eliminated comedication were identified as possible influencing factors that warrant further investigation.

Amoxicillin Blood Concentration in High-Dose Intravenous Discontinuous Amoxicillin: Look Beyond Numbers. Max-Amox Study.

High doses of amoxicillin are recommended to treat severe infections such as endocarditis. Amoxicillin causes dose-dependent toxicities, in particular crystal nephropathy. Toxicity could be avoided by monitoring of amoxicillin trough plasma concentrations (ATPC). However, the relevance of ATPC testing in routine medical practice remains poorly studied. We conducted a prospective clinical trial in adults treated with high doses of discontinuous intravenous amoxicillin in a French university hospital. The primary outcome was the distribution of ATPCs over three days during the first week of treatment. Urine tests for amoxicillin crystalluria (AC), pH, and density were also performed. Seventy patients were included. Overall intra-class correlation (ICC) was 0.35 IC95% [0.21; 0.53] with the following pairwise concordances: D1-D4 (n= 55) 0.23 IC95% [-0.02; 0.47], D1-D7 (n= 47) 0.41 IC95% [0.19; 0.63], and D4-D7 (n= 50) 0.17 IC95% [-0.10; 0.43]. Inter-individual variability was also significant, with coefficients of variation being 0.87 at D1, 1.20 at D4, and 1.35 at D7. AC occurred in 32 patients (47.8%). Risk of AC increased when pH was below or equal to 6 (P = 0.002). ATPCs were higher in patients with AC and/or acute kidney injury. Variability in ATPC was high and ATPC cannot be considered as the only monitoring tool to adjust amoxicillin dosage. High ATPC, low urinary pH, and presence of AC can alert physicians to a potential iatrogenic effect and lead to the decision to hydrate the patient, alkalinize urine and decrease the dosage of amoxicillin.

Effects of the Japanese Kampo Medicines Rikkunshito, Shakuyakukanzoto and Goreisan on Lenvatinib Plasma Concentrations in Japanese Patients with Thyroid Cancer.

Kampo medicines are often used in Japan as therapy for the side effects induced by oral kinase inhibitors. However, the pharmacokinetic interactions between Kampo medicines and oral kinase inhibitors such as lenvatinib have not been studied. We investigated the effects of Kampo medicines (rikkunshito, shakuyakukanzoto and goreisan) on the steady-state plasma trough concentration (C0) of lenvatinib in patients with thyroid cancer. Thirty-nine patients receiving lenvatinib therapy at Ito Hospital between May 2015 and December 2019 were enrolled. The mean C0 of lenvatinib with Kampo medicine, at the same dose as before initiating Kampo medicines, was used. After the repeated administration of rikkunshito (n = 21), shakuyakukanzoto (n = 10) or goreisan (n = 8), the mean C0 of lenvatinib and the laboratory test values of patients did not change significantly. In contrast to rikkunshito, which alleviates emesis by enhancing gastric emptying, the C0 values of lenvatinib with a proton pump inhibitor (PPI) (n = 16) or histamine H2 receptor antagonist (H2RA) (n = 4) were significantly lower than the C0 values without a PPI or H2RA (P = 0.007). The mean (range) change rate of the C0 of lenvatinib with a PPI or H2RA versus without a PPI or H2RA was 88.6% (69.9-115%), and was significantly greater than the change rate for rikkunshito (P = 0.029). There was no significant difference between the C0 of lenvatinib with a prokineticagent (n = 7) versus without a prokinetic agent (P = 0.365). Although these Kampo medicines are reported to inhibit drug-metabolizing enzymes and drug transporters, the risk of drug interactions for patients receiving lenvatinib therapy is low. Patients should feel confident that they can receive Kampo medicines as supportive care for lenvatinib therapy without a risk of drug interactions that could affect treatment efficacy.

Zeolites – tabletting ibuprofen with and without zeolites as an excipient

Abstract Introduction Drug delivery via the oral route is a patient and industry-preferred approach. However, maintaining plasma concentrations of the active pharmaceutical ingredient (API) within the therapeutic window can be challenging with immediate-release (IR) tablets. To avoid the plasma peaks and troughs associated with IR tablets, sustained release (SR) formulations have been investigated. Zeolites are microporous aluminosilicate minerals that represent a novel tabletting material with the potential for modifying drug release due to their unique adsorption and ion exchange properties1. Aim This study will investigate the potential for inclusion of zeolites within orally disintegrating tablets (ODTs) and assessment of their ability to modify API release. Methods In-house, 50%w/w ibuprofen (IBU)-loaded ODTs (IHODTs) were prepared from Pearlitol® Flash, magnesium (Mg) stearate and 2 different zeolites (CP814C and CP814E), incorporated at 5%w/w each, using a manual tablet press. Formulations were prepared and mixed for 10 minutes in a cube mixer prior to direct compression (DC) into tablets. Physical characteristics of the tablets were assessed by hardness and friability measurements. Tablet quality was assessed by disintegration and dissolution analysis to British Pharmacopeia (BP) standards2. Release profiles were assessed against various models to determine the effect of zeolites on the release of IBU. Formulations were further examined and characterised using scanning electron microscopy (SEM) and energy-dispersive x-ray (EDX) spectroscopy. An ethics evaluation was completed, and the study was identified as not having any ethical considerations by the University of South Wales. Results The mean weight of blank ODTs was found to be 225.3mg, with a mean thickness of 3.65mm, diameter of 8.10mm, hardness of 43.9±9.2N (mean±SD, n=5) and friability of 0.2±0.2% (mean±SD, n=3). The hardness of IHODTs was found to be 59.98±1.6N, reducing to 54.9±4.3N and 43.4±0.7N (mean±SD, n=3) with the inclusion of CP814C and CP814E, respectively. The friability of IHODTs containing zeolites was 1.76±0.4% and 1.91±0.9N (mean±SD, n=3), for CP814C and CP814E, respectively; conforming to BP specification2. The disintegration time for all in-house tablets, both with and without a zeolite included, was found to be an order of magnitude greater than commercial ODTs (CT) controls, but all remained within the BP specification2. The release of IBU from IHODTs and CTs showed good correlation to the first-order release model (R2 = 0.96 and 0.98, respectively), indicating IR behaviour. Similarly, the release of IBU from IHODTs containing zeolites was shown to correlate best with the first-order release model, R2 = 0.91 for CP814C and R2 = 0.90 for CP814E, respectively. SEM analysis suggested a homogeneous blend of components within IHODTs, whilst EDX analysis indicated the presence of silicon and aluminium from zeolites, and Mg and carbon from Mg stearate and IBU, respectively. Discussion / Conclusion This study investigated the effect of zeolite inclusion on the release properties of ODTs containing IBU. Although the quality of ODTs containing zeolites was not compromised, this study suggests that inclusion of a zeolite by DC only, does not significantly modify the release profile. Future studies are required to ascertain whether zeolites can achieve SR from ODTs using alternative API loading approaches, such as solvent loading1.

Therapeutic drug monitoring of tenofovir disoproxil and emtricitabine in oral HIV pre-exposure prophylaxis (PrEP) users who have undergone gastrointestinal surgery.

Oral HIV pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV, but its efficacy depends on adequate absorption of drug, which may decrease following gastrointestinal surgery. Clinicians across eight Genito-urinary Medicine clinics in the United Kingdom submitted data on PrEP users with history of gastrointestinal surgery who were referred to a national complex PrEP multi-disciplinary team between June 2021 and April 2023. Anonymised data were submitted on demographics, surgical history, PrEP regimen, and results of therapeutic drug monitoring (TDM) and HIV screening tests. Descriptive analyses were performed in SPSS version 29. Nine cases described cis-gender men-who-have-sex-with-men (MSM) with median age of 47.4 years (IQR = 43 - 56.5) taking tenofovir disoproxil (TDF)/emtricitabine (FTC) daily (n = 8) or event-based (n = 1) as PrEP. Median time between PrEP initiation and TDM was 53 days (IQR = 8.5-1705). The mean (±SD) trough concentration of tenofovir (TFV) and FTC were 90.2 ± 27.7ng/mL and 76.0 ± 45.9ng/mL, respectively. All patients had a negative HIV test at follow-up. Plasma trough concentrations of TFV observed in our cohort taking TDF/FTC were above the expected concentrations associated with PrEP efficacy as previously described in the literature, suggesting that PrEP can be safely given in this population, with TDM used for reassurance.

Drug monitoring was conducted for rifapentine among people with HIV receiving dolutegravir containing antiretroviral therapy and latent tuberculosis treatment

The proportion of trough plasma concentration of dolutegravir (DTG) above protein adjusted 90% inhibition concentration (IC90) (0.064mg/L) was 98.1% across all visits during the twelve doses of once-weekly rifapentine and isoniazid (3HP) in people with HIV (PWH). Furthermore, the participants maintained a high rate of HIV viral suppression (98%) within 6 months after completing 3HP.

Analysis of Nirmatrelvir Entry into Pulmonary Lining Fluid in Patients with COVID-19: A Unique Perspective to Explore and Understand the Target Plasma Concentration of 292 ng/mL in Antiviral Activity.

Currently, the applicant has chosen a target plasma trough concentration for nirmatrelvir, which is adjusted to 292 ng/mL based on the drug's molecular weight (499.54 Daltons), its binding to human plasma proteins (69%), and the in vitro antiviral EC90 value (181 nM). However, the current exposure-effect relationships (ER) analysis of viral load in patients enrolled in the EPIC-HR study has not revealed clinically significant trends in the ER. Given that the lungs are the primary site of COVID-19 infection, we aim to further understand this exposure relationship by exploring and analyzing the penetration characteristics of nirmatrelvir in the lungs. To explore and understand the target plasma concentration of 292 ng/mL in antiviral activity. We identified all critically ill patients with coronavirus disease 2019 who received nirmatrelvir/ritonavir treatment in the respiratory intensive care unit of Changhai hospital between January 2023 and October 2023. Samples of plasma and bronchoalveolar lavage fluid were obtained at pre-dose trough concentrations after administration of nirmatrelvir (NMV). The relationship between NMV levels in plasma and the epithelial lining fluid (ELF) was assessed by determining concentrations of NMV. There was a significant relationship between NMV levels in plasma and ELF (ELF = 0.4976*PLASMA- 204; R = 0.96), with a correlation whose slope (0.4976) suggested that the blood-to-ELF ratio of drug penetration was 2:1. A negative value from the equation indicates that NMV requires to reach baseline concentration to penetrate the ELF. The relationship between NMV levels in plasma and ELF with low permeability and a negative baseline value suggests that the target plasma concentration of 292 ng/mL is insufficient for antiviral activity. This study provides a unique perspective to explore and understand no clinically meaningful trend of exposure-response relationships in patients enrolled in EPIC-HR.

Effect of inflammation on voriconazole levels in patients with invasive pulmonary aspergillosis.

Voriconazole (VCZ) serum concentrations may be affected by many factors, such as drug-drug interactions, liver dysfunction, genetic polymorphism, and inflammation. This study aimed to determine the relationship between VCZ measured trough plasma levels and C-reactive protein levels in patients with coronavirus disease 2019 (COVID-19)-associated aspergillosis (CAPA) and invasive pulmonary aspergillosis (IPA). Patients who were > 18 years of age, received VCZ treatment for IPA or CAPA in our hospital between March 2020 and April 2021, and had their VCZ level monitored, were included in this retrospective study. A total of 85 patients (35 diagnosed with CAPA) were included in this study. Forty-three patients (50.6%) had VCZ levels in the therapeutic range, 4 (4.7%) were sub-therapeutic, and 38 (44.7%) were supra-therapeutic. Inflammatory markers were significantly higher in patients with supra-therapeutic levels (p < 0.05). Supra-therapeutic levels and VCZ-related adverse effects were significantly more frequent in CAPA patients than in IPA patients (p = 0.011 and p = 0.002, respectively). Patients diagnosed with CAPA were more prone to adverse effects and supra-therapeutic VCZ levels. More frequent therapeutic drug monitoring is recommended in this patient population.

Therapeutic drug monitoring and safety of voriconazole in patients with liver dysfunction.

This study aims to describe the distribution characteristics of voriconazole (VRC) plasma trough concentrations (Ctrough) in patients with liver dysfunction, identify factors influencing VRC Ctrough, and provide recommendations for the use of VRC in this population. We retrospectively collected medical records of hospitalized patients with liver dysfunction who used VRC and underwent therapeutic drug monitoring (TDM) at the First Hospital of Changsha. The severity of liver dysfunction was assessed by the Child-Pugh (CP) score. Multiple linear regression was employed to explore factors affecting VRC Ctrough in these patients. A total of 147 Ctrough from 102 patients with liver dysfunction were analyzed. Patients were categorized into a control group (n = 40), CP-A (n = 39), CP-B (n = 11), and CP-C group (n = 12). The initial probability of target attainment of Ctrough was 70.6%, with 6.9% of patients obtaining subtherapeutic Ctrough and 22.5% obtaining supertherapeutic Ctrough. The initial Ctrough in CP-A and B were 5.05 (0.64-9.57) mg/L and 5.37 (0.26-10.01) mg/L, respectively, significantly higher than the control group (P = 0.021 and P = 0.010). The proportion of VRC Ctrough of >5.5 mg/L in CP-A and B was 33.3% and 45.5%, respectively. Multiple linear regression analysis revealed that factors such as age ≥70 years, CP class, C-reactive protein (CRP), and direct bilirubin were significantly related to the initial VRC Ctrough. Among all measurements, patients with severe inflammation (CRP >100 mg/L), aged ≥70 years, and albumin levels of <30 or <25 g/L had significantly higher VRC Ctrough. The treatment success rate of VRC was 69.6% (71 of 102), and the rate of VRC-related adverse drug reactions was 29.4% (30 of 102). The recommended half-maintenance dose may lead to elevated VRC Ctrough in patients with CP-A and CP-B. TDM is essential for patients with advanced age, severe infections, or hypoalbuminemia to prevent excessive VRC trough levels.

The Influence of High Body Mass Index (BMI > 35 kg/m2) on Apixaban Plasma Concentration in Patients with Atrial Fibrillation.

Apixaban, a direct oral anticoagulant is administered for stroke prevention in atrial fibrillation patients. Dosing adjustment is guided by renal function, age, and body weight. However, no data exist on its pharmacokinetics in patients with a body mass index (BMI) ≥ 35 kg/m2. The aim was to investigate the effects of BMI ≥35 kg/m2 on trough plasma concentrations of apixaban in patients with atrial fibrillation. This prospective study compared steady-state trough concentrations of apixaban in patients with a BMI ≥35 kg/m2 and patients with a BMI <35 kg/m2. Sixty patients were included. In patients receiving 5 mg apixaban twice daily, the median trough plasma concentration was 29% lower in patients with a BMI ≥35 kg/m2 than in those with a BMI <35 kg/m2 (148.9 ng/ml, interquartile range [IQR] 94.5-205.6, compared to 209.1 ng/ml, IQR 167-266.8 ng/ml, respectively; P = 0.044). However, median trough concentrations fell within the manufacturer's predicted range for effective steady-state apixaban exposure. A similar trend was observed with 2.5 mg apixaban twice daily, although statistical significance was not reached. Multivariate analysis revealed no correlation between BMI values and trough concentrations. BMI ≥35 kg/m2 patients exhibited lower apixaban trough concentrations, while remaining within the manufacturer's established range for effective steady-state apixaban, suggesting that dose adjustment is unnecessary for this specific patient group.

Association between trough plasma voriconazole concentration and adverse drug reactions in elderly patients.

Only limited data are available on trough plasma voriconazole concentration in elderly patients. This study aimed to assess the association between voriconazole concentration and adverse drug reactions (ADR). A retrospective analysis was conducted to investigate the correlation between voriconazole trough concentration and adverse reactions among elderly patients admitted between October 1, 2017, and September 30, 2020. In total 147 patients were included in this study, with 248 measurements of voriconazole concentrations available. ADR occurred in 75 patients after drug therapy, with liver injury showing the highest incidence (n = 37, 49.33%), followed by hypokalemia (n = 27, 36%), and neurological disorder (n = 20, 26.67%). 121 measurements (48.79%) in 82 patients (55.78%) showed that the monitored trough concentration did not match the occurrence of ADR, mainly including hyponatremia, hypokalemia, liver injury, and kidney injury. The accuracy of predicting the trough concentration of voriconazole as recommended by current guidelines for elderly patients might be limited. Consequently, it is advisable to establish a tailored treatment range of voriconazole concentration specifically catered to this patient demographic.

Therapeutic Drug Monitoring of Imatinib: Is There a Rationale for Also Quantifying Its Active Metabolite?

Introduction: Therapeutic drug monitoring of imatinib is widely performed to individualize imatinib dosage. While N-desmethyl imatinib is an active metabolite of imatinib, its concentrations are not routinely determined. Methods: Imatinib and N-desmethyl imatinib trough plasma concentrations at steady-state were obtained from 295 patients with either chronic myeloid leukemia or gastrointestinal stromal tumor to see whether N-desmethyl imatinib provided additional information. Pharmacokinetic data were analyzed using a nonlinear mixed effect approach. Correlations between several pharmacokinetic metrics of drug exposure were evaluated. Results: The mean value of the N-desmethyl imatinib/imatinib ratio of trough concentrations was 0.31 with half of the values between 0.23 and 0.37. N-desmethyl imatinib and total (i.e., N-desmethyl imatinib plus imatinib) trough plasma concentrations or area under the curve values were closely correlated with imatinib values. The distribution of imatinib or total concentrations between patients requiring imatinib dosage adjustment, or not, was similar. Conclusion: These results do not clearly support routine N-desmethyl monitoring since it does not provide additional information to imatinib data.

Dried Blood Spots Sampling and Population Pharmacokinetic Modeling for Dosing Optimization of Piperacillin in Chinese Neonates.

Piperacillin is commonly used off-label in neonates for the treatment of bacterial infections. This study aimed to assess a dried blood spots (DBS)-based microsampling strategy for supporting population pharmacokinetics and treatment optimization of piperacillin in Chinese neonates. DBS samples from neonatal patients were collected at predefined intervals. Drug blood concentrations were quantified using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic model was developed using a nonlinear mixed-effects modeling approach. The pharmacokinetic/pharmacodynamics (PK/PD) target was 75% of the time with the unbound drug plasma concentration above the minimum inhibitory concentration (fT>MIC), with a toxicity threshold of unbound drug plasma trough concentration above 64 mg/L. A total of 45 piperacillin samples from 24 neonates were collected. The pharmacokinetics of piperacillin was described using a one-compartment model with postmenstrual age (PMA) as the most significant covariate on clearance. Simulations showed that dosing regimens achieving >90% PK/PD target attainment with <10% risk of possible toxicity were: PMA 33-35 weeks (50 mg/kg q12h), 35-37 weeks (50 mg/kg q8h), and 37-41 weeks (50 mg/kg q6h). In conclusion, Using DBS sampling, we developed a population pharmacokinetic model of piperacillin in Chinese neonates, incorporating PMA to determine optimal dosing regimens.

Factors influencing valproic acid trough levels in epileptic children.

In this study, we aimed to assess main factors influencing the Valproic Acid (V.Acid) plasma trough levels (C0) and to determine their degree of influence on V.Acid C0 in children with epilepsy who had Therapeutic Drug Monitoring (TDM). We conducted an observational study in the Department of Clinical Pharmacology including patients with generalized seizures' epilepsy aged between two and 18 years. Only the children that had benefited from at least two V.Acid C0 determinations were included. First, we assessed daily dose optimization, performed by the practitioners. Then we divided our population into two groups: group A with a final V.Acid C0 in the therapeutic range (TR) and group B with a final V. Acid C0 outside the TR to find out factors influencing V.Acid C0 journey. We included 805 patients (2537 V.Acid C0). The median age was 6.24 years and the sex ratio (M/F) was 1.45. The median V.Acid normalized daily dose was 27.27mg/kg/day and the median V.Acid C0 was 57µg/mL. The children's first V.Acid C0 was in the TR in 59.4% and V.Acid daily dose optimization was performed by the practitioners in 72.3%. Comparing GroupA and B, we found that age and the number of V.Acid C0 determinations increases the chance to reach the TR by respectively 3.79% and 7.39%. Older children who benefit from higher number of performed V.Acid C0 were more likely to reach the TR. In children who beneficiate from a TDM of V.Acid, close follow-up is mandatory to reach and maintain therapeutic V.Acid C0.

Промежуточные результаты российского проспективного многоцентрового клинического исследования READIT-2020 (снижение дозы ингибиторов тирозинкиназ при ХМЛ, концентрация иматиниба/нилотиниба в плазме, сохранение молекулярного ответа, лекарственная токсичность)

AIM. To measure the trough and maximum plasma concentrations of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients on standard and reduced doses of the drugs, to evaluate the impact of TKI plasma concentration on the loss of major/deep molecular response (MR) after dose reduction and the impact of TKI plasma concentration on drug toxicity changes. MATERIALS &amp; METHODS. The trial enrolled 46 imatinib and 16 nilotinib recipients. The trough (Сtrough) and maximum (Cmax) TKI plasma concentrations were measured. On imatinib/nilotinib therapy, Ctrough was analyzed in 104/22 and Cmax was analyzed in 63/15 plasma samples, respectively. RESULTS. The mean plasma imatinib Ctrough values on daily 400 mg, 300 mg, and 200 mg of the drug were 1092 ± 346 ng/mL, 809.5 ± 313.0 ng/mL, and 570.9 ± 280.0 ng/mL, respectively. The mean plasma imatinib Cmax on daily 300 mg and 200 mg were 1944 ± 577 ng/mL and 1233.4 ± 44.0 ng/mL, respectively. In the group of patients without deep MR-loss, on daily 300 mg and 200 mg imatinib, the mean plasma Ctrough values were 773.5 ± 303.0 ng/mL and 586.3 ± 308.0 ng/mL, and the mean Cmax values were 1866.5 ± 532.0 ng/mL and 1283.7 ± 481.0 ng/mL, respectively. In the group of patients with deep MR-loss, on daily 300 mg and 200 mg imatinib, the mean plasma Ctrough values were 774.8 ± 553.0 ng/mL and 490.6 ± 175.0 ng/mL, and the mean Cmax values were 2246 ± 1171 ng/mL and 1124.7 ± 281.0 ng/mL, respectively (p &gt; 0.05). The mean plasma imatinib Ctrough values on daily 400 mg, 300 mg, and 200 mg of the drug in the group of patients with drug toxicity were 1120.6 ± 303.0 ng/mL, whereas in the group without adverse effects these values were 998.4 ± 402.0 ng/mL (p = 0.09). The mean nilotinib Ctrough values on daily 600 mg, 400 mg, and 200 mg were 651.4 ± 397.0 ng/mL, 468.7 ± 220.0 ng/mL, and 376.7 ± 151.0 ng/mL, respectively. The mean nilotinib Cmax values on daily 400 mg and 200 mg were 655.3 ± 189.0 ng/mL and 628 ± 293 ng/mL, respectively. CONCLUSION. This clinical trial yielded differences in plasma imatinib Ctrough and Cmax values in CML patients treated with standard and reduced doses of the drug, which turned out to be significant (p &lt; 0.05). No significant differences in plasma nilotinib Ctrough and Cmax were identified. This trial revealed no significant differences in plasma imatinib Ctrough and Cmax on daily 400 mg and 300 mg of the drug in the groups of patients with and without adverse events. However, while dividing plasma imatinib Ctrough values during the period of 400 mg per day administration into 4 quartiles (Q1 and Q4 included patients with the lowest and the highest Ctrough values, respectively), the proportion of patients with drug toxicity appeared to be the highest in Q4 and accounted for 90 %.

A multi-centre, tolerability study of a cannabidiol-enriched Cannabis Herbal Extract for chronic headaches in adolescents: The CAN-CHA protocol

Introduction Cannabis products have been used in the management of headaches in adults and may play a role in pediatric chronic pain. Canadian pediatricians report increasing use of cannabis for the management of chronic headaches, despite no well-controlled studies to inform its dosing, safety, and effectiveness. The aim of our clinical trial is to determine the dosing and safety of a Cannabidiol (CBD)-enriched Cannabis Herbal Extract (CHE) for the treatment of chronic headaches in adolescents. Methods and analysis Youth, parents, and an expert steering committee co-designed this tolerability study. Twenty adolescents (aged 14 to 17 years), with a chronic migraine diagnosis for more than 6 months that has not responded to other therapies will be enrolled into an open label, dose escalation study across three Canadian sites. Study participants will receive escalating doses of a CBD-enriched CHE (MPL-001 with a THC:CBD of 1:25), starting at 0.2–0.4 mg/kg of CBD per day and escalating monthly up to 0.8–1.0 mg/kg of CBD per day. The primary objective of this study is to determine the safety and tolerability of CBD-enriched CHE in adolescents with chronic migraine. Secondary objectives of this study will inform the development of subsequent randomized controlled trials and include investigating the relationship between the dose escalation and change in the frequency of headache, impact and intensity of pain, changes in sleep, mood, function, and quality of life. Exploratory outcomes include investigating steady-state trough plasma levels of bioactive cannabinoids and investigating how pharmacogenetic profiles affect cannabinoid metabolism among adolescents receiving CBD-enriched CHE. Discussion This protocol was co-designed with youth and describes a tolerability clinical trial of CBD-enriched CHE in adolescents with chronic headaches that have not responded to conventional therapies. This study is the first clinical trial on cannabis products in adolescents with chronic headaches and will inform the development of future comparative effectiveness clinical trials. Trial registration CAN-CHA trial is registered with ClinicalTrials.gov with a number of register NCT05337033.