High Pharmacokinetic Variability Research Articles

New Predictive Equation for the Estimation of Plasma Concentrations of Formed Colistin in Patients Treated with Colistimethate Sodium for Multidrug-Resistant Gram-Negative Bacterial Infections.

The clinical use of colistin methanesulphonate (CMS) is limited by potential nephrotoxicity. The selection of an efficient and safe CMS dose for individual patients is complicated by the narrow therapeutic window and high interpatient pharmacokinetic variability. In this study, a simple predictive equation for estimating the plasma concentration of formed colistin in patients with multidrug and extremely drug-resistant gram-negative bacterial infections was developed. The equation was derived from the largest clinical cohort of patients undergoing therapeutic drug monitoring (TDM) of colistin for over 8 years in a tertiary Spanish hospital. All variables associated with Css,avg were selected in a multiple linear regression model that was validated in a second cohort of 40 patients. Measured Css,avg values were compared with those predicted by our model and a previous published algorithm for critically ill patients. In total, 276 patients were enrolled [the mean age was 67.2 (13.7) years, 203 (73.6%)] were male, and the mean (SD) Css,avg was 1.12 (0.98) mg/L. Age, gender, estimated glomerular filtration rate, CMS dose and frequency, and concomitant drugs were included in the model. In the external validation, the previous algorithm appeared to yield more optimized colistin plasma concentrations when all types of Css,avg values (high and low) were considered, while our equation yielded a more optimized prediction in the subgroup of patients with low colistin plasma concentrations (Css,avg <1.5 mg/L). The proposed equation may help clinicians to better use CMS among a wide variety of patients, to maximize efficacy and prevent nephrotoxicity. A further prospective PK study is warranted to externally validate this algorithm.

Therapeutic Drug Monitoring of Olanzapine: Effects of Clinical Factors on Plasma Concentrations in Psychiatric Patients.

Therapeutic drug monitoring (TDM) is strongly recommended for olanzapine due to its high pharmacokinetic variability. This study aimed to investigate the impact of various clinical factors on olanzapine plasma concentrations in patients with psychiatric disorders. The study used TDM data from the PsyMetab cohort, including 547 daily dose-normalized, steady-state, olanzapine plasma concentrations (C:D ratios) from 248 patients. Both intrinsic factors (eg, sex, age, body weight) and extrinsic factors (eg, smoking status, comedications, hospitalization) were examined. Univariate and multivariable, linear, mixed-effects models were employed, with a stepwise selection procedure based on Akaike information criterion to identify the relevant covariates. In the multivariable model (based on 440 observations with a complete data set), several significant findings emerged. Olanzapine C:D ratios were significantly lower in smokers (β = -0.65, P < 0.001), valproate users (β = -0.53, P = 0.002), and inpatients (β = -0.20, P = 0.025). Furthermore, the C:D ratios decreased significantly as the time since the last dose increased (β = -0.040, P < 0.001). The male sex had a significant main effect on olanzapine C:D ratios (β = -2.80, P < 0.001), with significant interactions with age (β = 0.025, P < 0.001) and body weight (β = 0.017, P = 0.011). The selected covariates explained 30.3% of the variation in C:D ratios, with smoking status accounting for 7.7% and sex contributing 6.9%. The overall variation explained by both the fixed and random parts of the model was 67.4%. The model facilitated the prediction of olanzapine C:D ratios based on sex, age, and body weight. The clinical factors examined in this study, including sex, age, body weight, smoking status, and valproate comedication, remarkably influence olanzapine C:D ratios. Considering these factors, in addition to TDM and the clinical situation, could be important for dose adjustment.

Abstract PO4-18-05: Safety and Feasibility of Administration of an Oral Cannabis Preparation in The Preoperative Period in Breast and Oral Cavity Cancer

Abstract Introduction- Cannabis is world’s oldest cultivated medicinal plant. It has potential applications in oncology, in reducing chronic pain, stimulating appetite, alleviating nausea/vomiting, improving overall well-being as well as its anti-cancer properties. We conducted a phase-1 dose escalation study to determine safety of pre-operative oral cannabis in breast and oral cavity squamous cell carcinoma (OC-SCC) with an intent to explore its anticancer potential in the “pre-operative” window. The primary objective was to determine maximum tolerated dose (MTD) and establish dose limiting toxicity (DLT). Secondary objectives were pharmacokinetic profiling and transcriptomic analysis of tumour tissue. Methodology- Primary objective was to determine maximum tolerated dose (MTD) and establish dose limiting toxicity (DLT). Secondary objectives were pharmacokinetic profiling and transcriptomic analysis of tumour tissue. Non-metastatic breast and OC-SCC patients planned for curative surgery were consented after thorough medical and mini-psychiatric evaluation with Brief Psychiatry Rating Scale (BPRS). The investigational product (IP) comprised of a capsule containing 2.5mg of tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD) in 100 mg monocrotolyn oil extract of dried leaves of C. sativa. The capsules were manufactured in an Ayurvedic GMP facility. The classical 3+3, phase-1 design used modified Fibonacci sequence for dose escalation, starting with 5mg THC+5mg CBD. Patients received IP once a day for 5 days after breakfast with hemodynamic and psychiatric monitoring and underwent the planned surgery on day-6. Pharmacokinetic samples were collected at predefined time-points and plasma levels of THC, 11-OH-THC, 11-COOH-THC and CBD were determined using a validated LC-MS/MS method. Tumour tissue was collected before 1st dose of cannabis and during surgery for biomarker analysis. Results- A total of 12 patients were enrolled (6-breast, 3-buccal mucosa, and 3-tongue cancers). First 3 patients completed the study without DLT at 5+5mg dose. A DLT was observed at dose level-2 (10+10mg) and therefore additional 3 patients were enrolled at the same dose. Two patients out of six at this dose had DLT (anxiety- grade-3 and somnolence- grade-2) necessitating dose de-escalation in the next cohort. At 7.5+7.5mg dose, all 3 patients tolerated the IP(MTD). Ten patients completed the study protocol. Common adverse effects were headache (2/12, grade-1), heavy head (8/12, grade-1), hypotension (2/12, grade-1 and 3), epigastric discomfort (1/12, grade-1), diarrhoea (1/12, grade-1), hyponatremia (1/12, grade-1), hypertension (1/12, grade-2), anxiety (1/12, grade-2). Pharmacokinetics of both CBD and THC was less than dose proportional. At the MTD (7.5+7.5), day-1 and day-5 AUC0-24 [median (range)] for CBD were 21.75 (12.44–41.44) ng/ml−1*h and 24.85 (13.72–35.93) ng/ml−1*h respectively. Similarly, for THC, day 1 and day 5 AUC0-24 were 11.79 (8.06–70.58) ng/ml−1*h and 68.98 (1.78 – 136.17) ng/ml−1*h, respectively. Significant accumulation of both CBD and THC was observed across all doses from day 1 to 5. A high variability in pharmacokinetics was observed for both constituents (CV Cmax = 101.26% and 117.48%; CV AUC0-24 = 102.50% and 112.37% for CBD and THC respectively. The median half-life of CBD and THC was 2.2 (1.6–10.7) and 1.9 (1.6–2.4) h respectively. There was no correlation observed between drug exposure and toxicity. There was no significant change in BPRS score before and after IP. Conclusion- We report the first phase-1 study of cannabis in breast and OC-SCC cancer in pre-operative setting for its anti-cancer potential. Biomarker analysis is awaited. MTD identified will be further explored in phase 2/3 clinical trials in breast, oral cavity, lung and pancreatic cancer with survival endpoints. Citation Format: Rajendra Badwe, Shalaka Joshi, Shiva Thiagarajan, Vikram Gota, Vaibhav Vanmali, Pallavi Daphale, Jayita Deodhar, Rohan Chaubal, Rohini Hawaldar, Jaya Chitra Aadhi, Saurabh Kumar Gupta, Delzaad Deolaliwala, Anil Bhansali, Siddhant Mistry, Satyajeet Singh, Nita Nair, Vani Parmar, Sudeep Gupta. Safety and Feasibility of Administration of an Oral Cannabis Preparation in The Preoperative Period in Breast and Oral Cavity Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-18-05.

Factors Influencing Quetiapine Pharmacokinetic Variability: A Review of Population Pharmacokinetics

Abstract: Atypical antipsychotic quetiapine (QTP) exhibits high pharmacokinetic variability and population pharmacokinetic (PopPK) analysis is one of the approaches used to characterize factors influencing QTP pharmacokinetic variability. Though QTP is not regarded as a narrow therapeutic index drug, knowledge of this area is of importance. Thus, this review was conducted to summarize significant predictors for QTP pharmacokinetic variability identified using a PopPK analysis and to explore any knowledge gaps to be investigated. PubMed, Scopus, and CINAHL Complete databases were searched for eligible studies, and 75 articles were identified. Of these, only five studies were included as they were conducted using a nonlinear mixed-effects approach. This review found that only limited predictors for QTP pharmacokinetics were identified, with body weight being a predictor for the volume of distribution and age and γ-glutamyl transpeptidase being predictors for QTP clearance. None of the studies included elderly patients aged &gt;65 years, and thus factors associated with aging were not investigated. Also, most of the participants in the PopPK analyses were from clinical trials which might not reflect real-world patients e.g., the impacts of polypharmacy may not be available. Moreover, while a population pharmacokinetic-pharmacodynamic model explaining QTP exposure and clinical response using the scores of the Brief Psychiatric Rating Scale is available, knowledge relevant to the relationship between exposure and QTP side effects has not been explored. Based on this limited information, future PopPK research encompassing a wide range of patient characteristics is required.

An LC-MS/MS Method for Quantification of Lamotrigine and Its Main Metabolite in Dried Blood Spots.

The antiepileptic drug lamotrigine (LTG) shows high pharmacokinetic variability due to genotype influence and concomitant use of glucuronidation inducers and inhibitors, both of which may be frequently taken by elderly patients. Our goal was to develop a reliable quantification method for lamotrigine and its main glucuronide metabolite lamotrigine-N2-glucuronide (LTG-N2-GLU) in dried blood spots (DBS) to enable routine therapeutic drug monitoring and to identify altered metabolic activity for early detection of drug interactions possibly leading to suboptimal drug response. The analytical method was validated in terms of selectivity, accuracy, precision, matrix effects, haematocrit, blood spot volume influence, and stability. It was applied to a clinical study, and the DBS results were compared to the concentrations determined in plasma samples. A good correlation was established for both analytes in DBS and plasma samples, taking into account the haematocrit and blood cell-to-plasma partition coefficients. It was demonstrated that the method is suitable for the determination of the metabolite-to-parent ratio to reveal the metabolic status of individual patients. The clinical validation performed confirmed that the DBS technique is a reliable alternative for plasma lamotrigine and its glucuronide determination.

Evidence for Therapeutic Drug Monitoring of Atypical Antipsychotics.

Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, are a newer class of antipsychotic drugs used to treat schizophrenia, bipolar disorder, and related psychiatric conditions. The plasma concentration of antipsychotic drugs is a valid measure of the drug at its primary target structure in the brain, and therefore determines the efficacy and safety of these drugs. However, despite the well-known high variability in pharmacokinetics of these substances, psychiatric medication is usually administered in uniform dosage schedules. Therapeutic drug monitoring (TDM), as the specific method that can help personalised medicine in dose adjustment according to the characteristics of the individual patient, minimizing the risk of toxicity, monitoring adherence, and increasing cost-effectiveness in the treatment, thus seems to be an elegant tool to solve this problem. Non-response to therapeutic doses, uncertain adherence to medication, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM of SGAs. This review aims to summarize an overview of the current knowledge and evidence of the possibilities to tailor the dosage of selected SGAs using TDM, including the necessary pharmacokinetic parameters for personalised pharmacotherapy.

Population pharmacokinetic model of rifampicin for personalized tuberculosis pharmacotherapy: Effects of SLCO1B1 polymorphisms on drug exposure

Rifampicin (RIF) exhibits high pharmacokinetic (PK) variability among individuals; a low plasma concentration might result in unfavorable treatment outcomes and drug resistance. This study evaluated the contributions of non- and genetic factors to the interindividual variability of RIF exposure, then suggested initial doses for patients with different weight bands. This multicenter prospective cohort study in Korea analyzed demographic and clinical data, the solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotypes, and RIF concentrations. Population PK modeling and simulations were conducted using nonlinear mixed-effect modeling. In total, 879 tuberculosis (TB) patients were divided into a training dataset (510 patients) and a test dataset (359 patients). A one-compartment model with allometric scaling for effect of body size best described the RIF PKs. The apparent clearance (CL/F) was 16.6% higher among patients in the SLCO1B1 rs4149056 wild-type group than among patients in variant group, significantly decreasing RIF exposure in the wild-type group. The developed model showed better predictive performance compared with previously reported models. We also suggested that patients with body weights of <40 kg, 40-55 kg, 55-70 kg, and >70 kg patients receive RIF doses of 450, 600, 750, and 1050 mg/day, respectively. Total body weight and SLCO1B1 rs4149056 genotypes were the most significant covariates that affected RIF CL/F variability in Korean TB patients. We suggest initial doses of RIF based on World Health Organization weight-band classifications. The model may be implemented in treatment monitoring for TB patients.

Effect of Obesity on the Pharmacokinetics and Pharmacodynamics of Anticancer Agents.

An objective of the Precision Medicine Initiative, launched in 2015 by the US Food and Drug Administration and National Institutes of Health, is to optimize and individualize dosing of drugs, especially anticancer agents, with high pharmacokinetic and pharmacodynamic variability. The American Society of Clinical Oncology recently reported that 40% of obese patients receive insufficient chemotherapy doses and exposures, which may lead to reduced efficacy, and recommended pharmacokinetic studies to guide appropriate dosing in these patients. These issues will only increase in importance as the incidence of obesity in the population increases. This publication reviews the effects of obesity on (1) tumor biology, development of cancer, and antitumor response; (2) pharmacokinetics and pharmacodynamics of small-molecule anticancer drugs; and (3) pharmacokinetics and pharmacodynamics of complex anticancer drugs, such as carrier-mediated agents and biologics. These topics are not only important from a scientific research perspective but also from a drug development and regulator perspective. Thus, it is important to evaluate the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents in all categories of body habitus and especially in patients who are obese and morbidly obese. As the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents may be highly variable across drug types, the optimal dosing metric and algorithm for difference classes of drugs may be widely different. Thus, studies are needed to evaluate current and novel metrics and methods for measuring body habitus as related to optimizing the dose and reducing pharmacokinetic and pharmacodynamic variability of anticancer agents in patients who are obese and morbidly obese.

Tacrolimus Pharmacokinetics is Associated with Gut Microbiota Diversity in Kidney Transplant Patients: Results from a Pilot Cross-Sectional Study.

Clinical use of tacrolimus (TAC), an essential immunosuppressant following transplantation, is complexified by its high pharmacokinetic (PK) variability. The gut microbiota gains growing interest but limited investigations have evaluated its contribution to TAC PKs. Here, we explore the associations between the gut microbiota composition and TAC PKs. In this pilot cross-sectional study (Clinicaltrial.gov NCT04360031), we recruited 93 CYP3A5 non-expressers stabilized kidney transplant recipients. Gut microbiota composition was characterized by 16S rRNA gene sequencing, TAC PK parameters were computed, and additional demographic and medical covariates were collected. Associations between PK parameters or diabetic status and the gut microbiota composition, as reflected by α- and β-diversity metrics, were evaluated. Patients with higher TAC area under the curve AUC/(dose/kg) had higher bacterial richness, and TAC PK parameters were associated with specific bacterial taxa (e.g., Bilophila) and amplicon sequence variant (ASV; e.g., ASV 1508 and ASV 1982 (Veillonella/unclassified Sporomusaceae); ASV 664 (unclassified Oscillospiraceae)). Building a multiple linear regression model showed that ASV 1508 (co-abundant with ASV 1982) and ASV 664 explained, respectively, 16.0% and 4.6% of the interindividual variability in TAC AUC/(dose/kg) in CYP3A5 non-expresser patients, when adjusting for hematocrit and age. Anaerostipes relative abundance was decreased in patients with diabetes. Altogether, this pilot study revealed unprecedented links between the gut microbiota composition and diversity and TAC PKs in stable kidney transplant recipients. It supports the relevance of studying the gut microbiota as an important contributor to TAC PK variability. Elucidating the causal relationship will offer new perspectives to predict TAC inter- and intra-PK variability.

Microneedle-mediated transdermal delivery of FK506 for treatment of acute cardiac allograft rejection

FK506 has been widely used to prevent acute rejection in heart transplantation (HT). However, its strong hydrophobicity, poor bioavailability, high pharmacokinetic variability, and narrow therapeutic window are obstacles to its application in HT. It has been demonstrated that localized and sustained immunosuppressant delivery may be a suitable route for FK506 administration. Hence, the objective of this study was to evaluate the efficacy of a FK506-loaded microneedle (FK506 MN) in the treatment of acute rejection in HT. The physicochemical properties of FK506 MN were evaluated, and it exhibited constant release over the course of at least 9 days with a 94.6 % cumulative release rate. Also, the FK506 MN treatment could successfully alleviate acute rejection and prolong allograft survival compared with the untreated group (mean survival time, 12.33 versus 7.25 days). Furthermore, T cell and macrophage infiltration as well as secretion of IL-2, IL-6 and IFN-γ were dramatically reduced in the FK506 MN group. As expected, no hepatoxicity and nephrotoxicity were observed after the application of FK506 MN. Taken together, FK506 MN based drug delivery system provides a novelty strategy to deliver FK506 in heart transplantation, which may be also suitable for other organ transplantations in the future.

Systems Biology and Peptide Engineering to Overcome Absorption Barriers for Oral Peptide Delivery: Dosage Form Optimization Case Study Preceding Clinical Translation.

Oral delivery of peptides and biological molecules promises significant benefits to patients as an alternative to daily injections, but the development of these formulations is challenging due to their low bioavailability and high pharmacokinetic variability. Our earlier work focused on the discovery of MEDI7219, a stabilized, lipidated, glucagon-like peptide 1 agonist peptide, and the selection of sodium chenodeoxycholate (Na CDC) and propyl gallate (PG) as permeation enhancer combinations. We hereby describe the development of the MEDI7219 tablet formulations and composition optimization via in vivo studies in dogs. We designed the MEDI7219 immediate-release tablets with the permeation enhancers Na CDC and PG. Immediate-release tablets were coated with an enteric coating that dissolves at pH ≥ 5.5 to target the upper duodenal region of the gastrointestinal tract and sustained-release tablets with a Carbopol bioadhesive polymer were coated with an enteric coating that dissolves at pH ≥ 7.0 to provide a longer presence at the absorption site in the gastrointestinal tract. In addition to immediate- and enteric-coated formulations, we also tested a proprietary delayed release erodible barrier layer tablet (OralogiKTM) to deliver the payload to the target site in the gastrointestinal tract. The design of tablet dosage forms based on the optimization of formulations resulted in up to 10.1% absolute oral bioavailability in dogs with variability as low as 26% for MEDI7219, paving the way for its clinical development.

Can we predict the influence of inflammation on voriconazole exposure? An overview.

Voriconazole is a triazole antifungal indicated for invasive fungal infections that exhibits a high degree of inter-individual and intra-individual pharmacokinetic variability. Voriconazole pharmacokinetics is non-linear, making dosage adjustments more difficult. Therapeutic drug monitoring is recommended by measurement of minimum plasma concentrations. Several factors are responsible for the high pharmacokinetic variability of voriconazole: age, feeding (which decreases absorption), liver function, genetic polymorphism of the CYP2C19 gene, drug interactions and inflammation. Invasive fungal infections are indeed very frequently associated with inflammation, which engenders a risk of voriconazole overexposure. Many studies have reviewed this topic in both the adult and paediatric populations, but few studies have focused on the specific point of the prediction, to evaluate the influence of inflammation on voriconazole pharmacokinetics. Predicting the impact of inflammation on voriconazole pharmacokinetics could help optimize antifungal therapy and improve patient management. This review summarizes the existing data on the influence of inflammation on voriconazole pharmacokinetics in adult populations. We also evaluate the role of C-reactive protein, the impact of inflammation on patient metabolic phenotypes, and the tools that can be used to predict the effect of inflammation on voriconazole pharmacokinetics.

B-335 Rapid Quantitative Clozapine Measurements at the Point-of-Care Using Capillary Blood

Abstract Background Clozapine is the most effective medication for treatment-resistant schizophrenia, and is endorsed in professional guidelines. Therapeutic drug monitoring (TDM) is recommended for Clozapine due to high pharmacokinetic variability and risk of adverse drug reactions. The effectiveness of TDM for managing clozapine patients is limited by the lack of immediate results. Methods A novel immunoassay, the MyCare Insite Clozapine Test (MCI), was developed that uses 20 µL of capillary blood (CP) and delivers 7-minute quantitative results for a portable point-of-care (POC) device. To validate the MCI system, matching CP and serum samples were collected from 113 patients at two sites. CP was tested immediately with MCI and compared to serum immunoassay results on a Beckman-Coulter AU480 analyzer. Precision was evaluated using three whole blood spiked samples and two assay controls over five days with five replicates per day. Results The figure shows a correlation plot evaluated by Passing-Bablok regression of the POC MCI (y-axis) and the Beckman analyzer (x-axis). The regression line was y = 1.05*x + 1.4 ng/L, r = 0.927, indicating good agreement. Precision studies demonstrated that repeatability was ≤11% and within-lab precision was ≤13%. Conclusion Quantitative Clozapine results are available in 7 min using CP in a portable POC device. A rapid POC alternative can achieve timely patient results in many testing environments. Rapid Clozapine testing has the potential for expanding utilization of this important drug by providing actionable POC results.

Population Pharmacokinetics and Pharmacogenetics Analyses of Dasatinib in Chinese Patients with Chronic Myeloid Leukemia.

Dasatinib, a second-generation tyrosine kinase inhibitor of BCR-ABL 1, used for first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML), exhibits high pharmacokinetic (PK) variability. However, its PK data in Chinese patients with CML remains rarely reported to date. Thus, we developed a population pharmacokinetic (PPK) model of dasatinib in Chinese patients and identified the covariate that could explain the individual variability of PK for optimal individual administration. PPK modeling for dasatinib was performed based on 754 plasma concentrations obtained from 140 CML patients and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was evaluated using internal and external validation. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages. The PK of dasatinib were well described by a two-compartment with a log-additive residual error model. Patients in the current study had a relatively low estimate of CL/F (126 L/h). A significant association was found between the covariate of age and CL/F of dasatinib, which was incorporated into the final model. None of the genetic factors was confirmed as a significant covariate for dasatinib. The results of external validation with 140 samples from 36 patients were acceptable. Simulation results showed significantly higher exposures in elderly patients. This study's findings suggested that low-dose dasatinib would be better suited for Chinese patients, and the dosage can be appropriately reduced according to the increase of age, especially for the elderly.

PEG 400 Ion Suppression in Busulfan Detection by High-Performance Liquid Chromatography-Tandem Mass Spectrometry.

Busulfan (Bu), an alkylating agent commonly used in chemotherapy and transplantation, exhibits high intraindividual pharmacokinetic variability and possible time-dependent variations in clearance, which complicate therapeutic drug monitoring. Numerous analytical methods have been developed to reduce analysis time and facilitate timely decision-making regarding treatment changes; however, the validation procedures rarely involve analysis of potentially interfering excipients. Macrogol 400 (PEG 400) should be considered as a possible interfering agent in the detection of plasma Bu levels, especially as an ionization suppressor. Six intravenous formulations of Bu were compared with identify at least 1 common excipient (PEG 400). During the 176 therapeutic drug monitoring analyses of Bu, one of the PEG 400 specific mass-to-charge ratio transitions was determined using an instrumental method. After coelution with Bu and its internal standard (Bu-d8) was confirmed, all analyses were repeated using a different experimental setup free of ion suppression induced by PEG. The concentration-time profile of PEG 400 was also analyzed. The area under the curve obtained from the 2 data sets was compared and analyzed using Lin concordance correlation coefficient and Bland-Altman plot analysis. The results from the 2 analytical methods were comparable: PEG 400 negatively affected the Bu-d8 coefficient of variation but not the Bu/Bu-d8 ratio. The possible interference of PEG 400 should be thoroughly investigated, especially with respect to analytical methods that cannot be supported by correction of the stable isotopically labeled internal standard analog.

A thin-film molecularly imprinted polymer for the measurement of tyrosine kinase inhibitors in human plasma

Tyrosine kinase inhibitors (TKIs) are a class of drugs that have found broad application in cancer therapies. These include imatinib, the first TKI used as an inhibitor of BCR-ABL kinase to treat chronic myelogenous leukemia, as well as second generation (e.g., nilotinib and dasatinib) and third generation (e.g., ponatinib) TKIs with increased potency, specificity, and binding site affinity specificity. Although the evolution of TKIs have brought dramatic increases to life expectancy, adverse events are likely due to the relatively high dosage required for treatment and the high pharmacokinetic variability between individuals. Therapeutic drug monitoring can be employed to fine tune the dosage for better control of the treatment. In this work, we present an extraction system that incorporates a novel molecularly imprinted polymer (MIP) capable of the rapid extraction of four TKIs: imatinib, nilotinib, dasatinib, and ponatinib from human plasma. The system is comprised of 96 thin-film microextraction devices in a standard flat-bottomed 96-well plate, which allows for rapid and reproducible concurrent TKIs extraction with determination by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Extraction, washing, and desorption protocols are simplified, with minimal manual handling and can be fully automated. Inter-device and batch-to-batch variability is low (∼5%), commending these for single-use applications. The linear ranges for all four TKIs are broad, with limits of detection and quantification far below the lowest clinically significant values and upper limits above the therapeutic ranges. Overall, these devices would be suitable for clinical applications or therapeutic drug monitoring of dasatinib, imatinib, nilotinib, and ponatinib, either individually or in any combination.

Antifungal Dosing in Critically Ill Patients on Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) is an established advanced life support system, providing temporary cardiac and/or respiratory support in critically ill patients. Fungal infections are associated with increased mortality in patients on ECMO. Antifungal drug dosing for critically ill patients is highly challenging because of altered pharmacokinetics (PK). PK changes during critical illness; in particular, the drug volume of distribution (Vd) and clearance can be exacerbated by ECMO. This article discusses the available literature to inform adequate dosing of antifungals in this patient population. The number of antifungal PK studies in critically ill patients on ECMO is growing; currently available literature consists of case reports and studies with small sample sizes providing inconsistent findings, with scant or no data for some antifungals. Current data are insufficient to provide definitive empirical drug dosing guidance and use of dosing strategies derived from critically patients not on ECMO is reasonable. However, due to high PK variability, therapeutic drug monitoring should be considered where available in critically ill patients receiving ECMO to prevent subtherapeutic or toxic antifungal exposures.

Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia.

Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). A two-compartment model was built using 483 data points from 45 patients (0.33-17.83years of age) treated with MTX (0.25-5g/m2) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as [Formula: see text]. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size.

Pharmacokinetics of Venetoclax Co-Administered with Posaconazole in Patients with Acute Myeloid Leukemia.

The Food and Drug Administration currently approves the combination of hypomethylating agents (HMA), azacytidine or decitabine with venetoclax (VEN) for acute myeloid leukemia (AML) patients aged more than 75 years and for patients unsuitable for intensive chemotherapy. The risk of fungal infection in the early phase of treatment is not negligible; therefore, posaconazole (PCZ) is commonly administered as primary prophylaxis. A drug-drug interaction between VEN and PCZ is well known, but the trend of serum levels of venetoclax when both drugs are overlapped is not clear. In total, 165 plasma samples from 11 elderly AML patients receiving combined treatment with HMA, VEN and PCZ were analyzed by a validated analytical method (high-pressure liquid chromatography-tandem mass spectrometry). Venetoclax trough plasma concentrations were detected during the 3 days of ramp-up as well as on day 7 and day 12 of treatment when the exposure as the area under the plasma concentration-time curve and the accumulation ratio were also calculated. The results were compared with the expected data for 400 mg/dose VEN administered alone-the confirmed high inter-individual variability in pharmacokinetics suggests the need for therapeutic drug monitoring.

Comparison of Three Renal Function Formulas for Ganciclovir/Valganciclovir Dose Individualization in CMV-Infected Solid Organ Transplantation Patients Using a Population Approach.

The gold standard treatment of established cytomegalovirus infection or prevention in solid organ transplantation is the intravenous administration of ganciclovir (GCV) or oral administration of valganciclovir (VGCV), both adjusted to the renal function. In both instances, there is a high interindividual pharmacokinetic variability, mainly owing to the wide range of variation of both the renal function and body weight. Therefore, accurate estimation of the renal function is crucial for GCV/VGCV dose optimization. This study aimed to compare three different formulas for estimating the renal function in solid organ transplantation patients with cytomegalovirus infection, for individualizing antiviral therapy with GCV/VGCV, using a population approach. A population pharmacokinetic analysis was performed using NONMEM 7.4. A total of 650 plasma concentrations obtained after intravenous GCV and oral VGCV administrations were analyzed, from intensive and sparse sampling designs. Three different population pharmacokinetic models were built with the renal function given by Cockcroft-Gault, Modification of Diet in Renal Disease, or Chronic Kidney Disease EPIdemiology Collaboration (CKD-EPI) formulas. Pharmacokinetic parameters were allometrically scaled to body weight. The CKD-EPI formula was identified as the best predictor of between-patient variability in GCV clearance. Internal and external validation techniques showed that the CKD-EPI model had better stability and performed better compared with the others. The model based on the more accurate estimation of the renal function with the CKD-EPI formula and body weight as a size metric most used in the clinical practice can refine initial dose recommendations and contribute to GCV and VGCV dose individualization when required in the prevention or treatment of cytomegalovirus infection in solid organ transplantation patients.