Intravenous (IV) busulfan doses are often personalized to a concentration at steady state (Css) using the patient's clearance, which is estimated with therapeutic drug monitoring. We sought to ...identify biomarkers of IV busulfan clearance using a targeted pharmacometabonomics approach. A total of 200 metabolites were quantitated in 106 plasma samples, each obtained before IV busulfan administration in hematopoietic cell transplant (HCT) recipients. Both univariate linear regression with false discovery rate (FDR) and pathway enrichment analyses using the Global test were performed. In the univariate analysis, glycine, N-acetylglycine, 2-hydroxyisovaleric acid, creatine, serine, and tyrosine were statistically significantly associated with IV busulfan clearance at P < 0.05, with the first three satisfying the FDR of q < 0.1. Using pathway enrichment analysis, the glycine, serine, and threonine metabolism pathway was statistically significantly associated with IV busulfan clearance at P < 0.05 and q < 0.1, and a pathway impact >0.1. Glycine is a component of glutathione, which is conjugated with busulfan via glutathione transferase enzymes. These results demonstrate the potential utility of pharmacometabonomics to inform IV busulfan dosing. Future studies are required to validate these findings.
Pharmacokinetic drug interactions precipitated by botanical and other natural products (NPs) remain critically understudied. Investigating these complex interactions is fraught with difficulties due ...to the methodologic and technical challenges associated with the inherently complex chemistries and product variability of NPs. This knowledge gap is perpetuated by a continuing absence of a harmonized framework regarding the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions. Accordingly, this Recommended Approach, the fourth in a series of Recommended Approaches released by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), provides recommendations for the design of clinical pharmacokinetic studies involving NPs. Building on prior Recommended Approaches and data generated from the NaPDI Center, such a framework is presented for the design of (1) phase 0 studies to assess the pharmacokinetics of an NP and (2) clinical pharmacokinetic NP‐drug interaction studies. Suggestions for NP sourcing, dosing, study design, participant selection, sampling periods, and data analysis are presented. With the intent to begin addressing the gap between regulatory agencies’ guidance documents about drug‐drug interactions and contemporary NPDI research, the objective of this Recommended Approach is to propose methods for the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions.
This paper focuses primarily on the data published in the last decade about the pharmacokinetics and pharmacodynamics of oral and intravenous (i.v.) busulfan, therapeutic drug monitoring and clinical ...outcome in hemato-poietic stem cell transplant (HCT) patients. Busulfan is commonly used in HCT as it is toxic to the marrow. Busulfan is available as oral or i.v. formulation. The most common significant toxicity of busulfan is sinusoidal obstruction syndrome. Even with the introduction of i.v. busulfan, variability in the systemic concentrations of busulfan after weight-based dosing and the association between busulfan plasma exposure and outcome in HCT patients have led to the continued use of therapeutic drug monitoring of busulfan. New strategies for personalizing busulfan dosing are being studied to maximize the use of busulfan for optimal disease control with the least toxicity to HCT patients. One such strategy currently being evaluated is if busulfan clearance can be accurately predicted by genetic polymorphism of glutathione S-transferase (GST), with the currently available data suggesting that GST polymorphisms cannot be used to personalize busulfan dosing.
Background
The number of patients undergoing autologous haematopoietic cell transplant (HCT) is growing, but little is known about the factors that predict adverse outcomes. Low muscle mass and ...obesity are associated with disability and premature mortality in individuals with non‐malignant diseases and may predict outcomes after autologous HCT.
Methods
This was a retrospective cohort study of 320 patients who underwent autologous HCT for Hodgkin or non‐Hodgkin lymphoma between 2009 and 2014. Sarcopenia {skeletal muscle index male: <43 cm/m2 body mass index (BMI) < 25 kg/m2 or < 53 cm/m2 BMI ≥ 25 kg/m2 and female: <41 cm/m2 regardless of BMI) and obesity total abdominal adiposity ≥450.0 cm2 (male), ≥396.4 cm2 (female) were assessed from single‐slice abdominal pre‐HCT computed tomography images. Length of hospital stay, first unplanned intensive care unit admission, and 30‐day unplanned readmission were evaluated based on body composition using multivariable regression analysis, and mortality was evaluated with Kaplan–Meier analysis and Gray's test.
Results
Median age at HCT was 53.3 years (range, 18.5 to 78.1 years); 26.3% were sarcopenic and an additional 7.8% were sarcopenic obese pre‐HCT. Sarcopenic obesity was associated with increased risk of prolonged hospitalization odds ratio (OR) = 3.6, 95% confidence interval (CI) 1.3–9.8, intensive care unit admission (OR = 4.7, 95% CI 1.5–16.1), and unplanned readmission after HCT (OR = 13.6, 95% CI 2.5–62.8). Patients who were sarcopenic obese also had the highest mortality risk at 1 year hazard ratio (HR): 3.9, 95% CI 1.1–11.0 and 5 years (HR: 2.5, 95% CI 1.1–5.5), compared with patients with normal body composition. Sarcopenia alone, but not obesity alone, was associated with an increased risk of these outcomes, albeit with a lower magnitude of risk than in patients who were sarcopenic obese.
Conclusions
Sarcopenic obesity was an important predictor of outcomes in patients undergoing autologous HCT. These findings could inform targeted prevention strategies in patients at highest risk of complications after HCT.
Green tea (
) is a popular beverage worldwide, raising concern for adverse interactions when co-consumed with conventional drugs. Like many botanical natural products, green tea contains numerous ...polyphenolic constituents that undergo extensive glucuronidation. As such, the UDP-glucuronosyltransferases (UGTs), particularly intestinal UGTs, represent potential first-pass targets for green tea-drug interactions. Candidate intestinal UGT inhibitors were identified using a biochemometrics approach, which combines bioassay and chemometric data. Extracts and fractions prepared from four widely consumed teas were screened (20-180
g/ml) as inhibitors of UGT activity (4-methylumbelliferone glucuronidation) in human intestinal microsomes; all demonstrated concentration-dependent inhibition. A biochemometrics-identified fraction rich in UGT inhibitors from a representative tea was purified further and subjected to second-stage biochemometric analysis. Five catechins were identified as major constituents in the bioactive subfractions and prioritized for further evaluation. Of these catechins, (-)-epicatechin gallate and (-)-epigallocatechin gallate showed concentration-dependent inhibition, with IC
values (105 and 59
M, respectively) near or below concentrations measured in a cup (240 ml) of tea (66 and 240
M, respectively). Using the clinical intestinal UGT substrate raloxifene, the
values were ∼1.0 and 2.0
M, respectively. Using estimated intestinal lumen and enterocyte inhibitor concentrations, a mechanistic static model predicted green tea to increase the raloxifene plasma area under the curve up to 6.1- and 1.3-fold, respectively. Application of this novel approach, which combines biochemometrics with in vitro-in vivo extrapolation, to other natural product-drug combinations will refine these procedures, informing the need for further evaluation via dynamic modeling and clinical testing.
Busulfan-based conditioning is the most commonly used high-dose conditioning regimen for allogeneic hematopoietic cell transplant (HCT). The alkylating agent busulfan has a narrow therapeutic index, ...with busulfan doses personalized to a target plasma exposure (targeted busulfan). Using a global pharmacometabonomics approach, we sought to identify novel biomarkers of relapse or acute graft versus host disease (GVHD) in a cohort of 84 patients receiving targeted busulfan before allogeneic HCT. A total of 763 endogenous metabolomic compounds (EMCs) were quantitated in 230 longitudinal blood samples before, during, and shortly after intravenous busulfan administration. We performed both univariate linear regression and pathway enrichment analyses using global testing. The cysteine/methionine pathway and the glycine, serine, and threonine metabolism pathway were most associated with relapse. The latter be explained by the fact that glutathione S-transferases conjugate both busulfan and glutathione, which contains glycine as a component. The d-arginine and d-ornithine metabolism pathway and arginine and proline metabolism pathway were most associated with acute GVHD. None of these associations were significant after correcting for false discovery rate (FDR) with a strict cutoff of FDR-adjusted p < 0.1. Although larger studies are needed to substantiate these findings, the results show that EMCs may be used as predictive biomarkers in HCT patients.
Abstract
Green tea is a popular beverage worldwide. The abundant green tea catechin (−)‐epigallocatechin gallate (EGCG) is a potent in vitro inhibitor of intestinal UDP‐glucuronosyltransferase (UGT) ...activity (
K
i
~2 μM). Co‐consuming green tea with intestinal UGT drug substrates, including raloxifene, could increase systemic drug exposure. The effects of a well‐characterized green tea on the pharmacokinetics of raloxifene, raloxifene 4′‐glucuronide, and raloxifene 6‐glucuronide were evaluated in 16 healthy adults via a three‐arm crossover, fixed‐sequence study. Raloxifene (60 mg) was administered orally with water (baseline), with green tea for 1 day (acute), and on the fifth day after daily green tea administration for 4 days (chronic). Unexpectedly, green tea decreased the geometric mean green tea/baseline raloxifene AUC
0–96h
ratio to ~0.60 after both acute and chronic administration, which is below the predefined no‐effect range (0.75–1.33). Lack of change in terminal half‐life and glucuronide‐to‐raloxifene ratios indicated the predominant mechanism was not inhibition of intestinal UGT. One potential mechanism includes inhibition of intestinal transport. Using established transfected cell systems, a green tea extract normalized to EGCG inhibited 10 of 16 transporters tested (IC
50
, 0.37–12 μM). Another potential mechanism, interruption by green tea of gut microbe‐mediated raloxifene reabsorption, prompted a follow‐up exploratory clinical study to evaluate the potential for a green tea–gut microbiota–drug interaction. No clear mechanisms were identified. Overall, results highlight that improvements in current models and methods used to predict UGT‐mediated drug interactions are needed. Informing patients about the risk of co‐consuming green tea with raloxifene may be considered.
The lack of effective treatment options for pancreatic cancer has led to a 5-year survival rate of just 8%. Here, we evaluate the ability to enhance targeted drug delivery using mild hyperthermia in ...combination with the systemic administration of a low-temperature sensitive liposomal formulation of doxorubicin (LTSL-Dox) using a relevant model for pancreas cancer.
Experiments were performed in a genetically engineered mouse model of pancreatic cancer (KPC mice: LSL-Kras
; LSL-Trp53
; Pdx-1-Cre). LTSL-Dox or free doxorubicin (Dox) was administered via a tail vein catheter. A clinical magnetic resonance-guided high intensity focussed ultrasound (MR-HIFU) system was used to plan treatment, apply the HIFU-induce hyperthermia and monitor therapy. Post-therapy, total Dox concentration in tumour tissue was determined by HPLC and confirmed with fluorescence microscopy.
Localized hyperthermia was successfully applied and monitored with a clinical MR-HIFU system. The mild hyperthermia heating algorithm administered by the MR-HIFU system resulted in homogenous heating within the region of interest. MR-HIFU, in combination with LTSL-Dox, resulted in a 23-fold increase in the localised drug concentration and nuclear uptake of doxorubicin within the tumour tissue of KPC mice compared to LTSL-Dox alone. Hyperthermia, in combination with free Dox, resulted in a 2-fold increase compared to Dox alone.
This study demonstrates that HIFU-induced hyperthermia in combination with LTSL-Dox can be a non-invasive and effective method in enhancing the localised delivery and penetration of doxorubicin into pancreatic tumours.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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