Implications of chronic moderate protein-deficiency malnutrition on doxorubicin pharmacokinetics and cardiotoxicity in early post-weaning stage.

BACKGROUND: Malnutrition is a common problem in developing countries, and the impact of severe malnutrition on optimal treatment outcomes of chemotherapy in pediatric cancer patients is well documented. However, despite being a more prevalent and distinct entity, moderate malnutrition is until now unexplored for its effects on treatment outcomes. AIMS: In this study we aimed to investigate the molecular basis of altered pharmacokinetics and cardiotoxicity of doxorubicin observed in early-life chronic moderate protein deficiency malnutrition. MATERIALS AND METHODS: We developed an animal model of early-life moderate protein-deficiency malnutrition and validated it using clinical samples. This model was used to study pharmacokinetic and toxicity changes and was further utilized to study the molecular changes in liver and heart to get mechanistic insights. KEY FINDINGS: Here we show that moderate protein-deficiency malnutrition in weanling rats causes changes in drug disposition in the liver by modification of hepatic ABCC3 and MRP2 transporters through the TNFα signalling axis. Furthermore, malnourished rats in repeat-dose doxorubicin toxicity study showed higher toxicity and mortality. A higher accumulation of doxorubicin in the heart was observed which was associated with alterations in cardiac metabolic pathways and increased cardiotoxicity. SIGNIFICANCE: Our findings indicate that moderate malnutrition causes increased susceptibility towards toxic side effects of chemotherapy. These results may necessitate further investigations and new guidelines on the dosing of chemotherapy in moderately malnourished pediatric cancer patients.

A Prospective Study to Evaluate the Effect of Therapeutic Drug Monitoring-Based Posaconazole Prophylaxis on Invasive Fungal Infection Rate During Acute Myeloid Leukemia Induction Therapy.

Invasive fungal infections (IFIs) are a significant cause of morbidity and mortality in de-novo acute myeloid leukemia patients receiving induction chemotherapy. Despite using posaconazole, a broad-spectrum antifungal, for IFI prophylaxis, the breakthrough IFI rate is high in the real-world setting. One of the reasons could be frequent suboptimal plasma posaconazole levels. In the present study, we evaluated if therapeutic drug monitoring (TDM) guided posaconazole prophylaxis can reduce the IFI rates in comparison to a historical cohort. We enrolled 90 patients, > / = 16 years of age, without baseline IFIs, planned for remission induction therapy. All patients were started on posaconazole suspension 200 mg TDS and the dose was increased in a stepwise manner if trough levels were found to be suboptimal (< 350 ng/ml for day 2 or < 700 ng/ml subsequently). The TDM based approach resulted in a significant decline in breakthrough IFI rates (18% versus 52%, P < 0.0001) A total of 69 patients (78%) required dose escalation. Thirty-one patients required change in antifungals due to either suboptimal levels, persistent fever, diarrhoea or vomiting. We could not demonstrate an exposure-response relationship but the difference in IFI rates in patients with a median posaconazole level > / = 700 ng/ml (0%) and < 700 ng/ml (21.6%) was clinically meaningful. Posaconazole levels were found to be significantly lower in patients on antacids and prokinetics. The incidence of posaconazole-related grade 3 toxicity was low (2.3%). Thus TDM-based dosing of posaconazole helps reduce breakthrough IFI rate and should be a part of posaconazole prophylaxis. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-023-01709-3.

Effect of Moderate Malnutrition on the Pharmacokinetics of Etoposide and Vincristine in Freshly Weaned Rats.

BACKGROUND: Moderate malnutrition is a common problem in young children. It is observed that severe malnutrition affects the pharmacokinetics of chemotherapy drugs in pediatric cancer patients, but moderate malnutrition is not well studied in this context. OBJECTIVES: In this study, we aimed to understand how moderate malnutrition affects the pharmacokinetics of two chemotherapy drugs, etoposide and vincristine, using a murine model of early age moderate malnutrition. METHODS: We developed a murine model of moderate childhood malnutrition by subjecting freshly weaned Sprague-Dawley rats to 8% protein diet for 8 weeks. In two separate experiments, we administered etoposide and vincristine (N = 8 for etoposide and N = 12 for vincristine each in protein deficient and control groups) through tail vein injection for pharmacokinetics study. RESULTS: We found ~ 60% increase in area under the concentration-time curve (AUC) of etoposide in malnourished animals as compared to well-nourished animals. Furthermore, clearance, volume of distribution, and half-life were decreased by ~ 37, 53, and 24%, respectively, in malnourished animals. Pharmacokinetic parameters of vincristine showed only marginal differences between well-nourished and malnourished groups. CONCLUSIONS: Our results suggest that while moderate malnutrition significantly affects the pharmacokinetics of etoposide, pharmacokinetics of vincristine remain unchanged. Since chemotherapy drugs have a narrow therapeutic index, the difference in AUC observed in our study might explain the increased toxicity of etoposide in malnourished pediatric cancer patients. This brings forth a need for robust clinical studies to validate our findings and optimize dose for malnourished patients.

Exposure-Response Relationship of Posaconazole Suspension in Theprophylaxis of Invasive Fungal Infections in Patients with Acute Myeloid Leukemia.

Purpose: Antifungal prophylaxis with posaconazole has demonstrated a reduction in the risk of death due to Invasive fungal infections (IFI)in patients with acute myeloid leukemia (AML) during induction therapy. However, various factors affect the plasma levels of posaconazole and can potentially limit its efficacy. Therapeutic drug monitoring (TDM) can help optimize the dose, but literature is scant from centers with a high IFI burden. This study aimed to evaluate the proportion of de-novo AML patients on induction who could achieve the target level of 700ng/mL with posaconazole prophylaxis,factors that can influence the plasma levels, and the impact of plasma posaconazole levels on incidence of IFI. Methods: Patients with AML on induction therapy with no baseline IFI were enrolled at our tertiary cancer center which has high prevalence of IFI. These patients received posaconazole suspension as prophylaxis. Daily plasma levels were measured from Day 4 till Day 12 of posaconazole prophylaxis. All patients were monitored for the development of IFI. The data on adverse events, concomitant drugs, mucositis, vomiting, and diarrhea were recorded. Results: A total of 411 samples from fifty patients were collected. Only 177 out of 411 samples had levels > 700 ng/mL. The median trough level was 610 ng/mL (range30-3000 ng/mL). The median time to achieve target trough concentration was four days (range 4-12 days) from the start of induction.Thirty-eight (76%) patients achieved target plasma levels by day 12 of induction.The median plasma level on day 12 was 690 ng/mL (range,30-1270) in patients who achieved target levels as compared to 340 (50-560) ng/mL in those who did not. Twenty-six (52%) patients had IFI in our study, and the median time to develop breakthrough IFI was 14 days (range 4-24 days). Median and range of plasma levels were 690 ng/ml (30-2410; n = 22) in those who developed IFI, while 590 ng/mL (50-2300 n = 24) in those who did not. The odds of developing IFI in patients who did not achieve the threshold trough concentration of 700 ng/mL was 7.14 (95% CI; 1.35-37.75, p = 0.0206). Occurrence of vomiting (p = 0.02), diarrhea (p = 0.0008), mucositis (p = 0.003) had adverse impact on achievement of target plasma posaconazole levels. Conclusion: A significant proportion of patients receiving posaconazole prophylaxis fail to achieve target plasma levels which can result in high risk of development of IFI. Occurrence of diarrhea, vomiting and mucositis can adversely affect the achievement target plasma levels.

A prospective, open-label, randomised, parallel design study of 4 generic formulations of intramuscular L-asparaginase in childhood precursor B-cell acute lymphoblastic leukaemia (ALL).

AIMS: L-asparaginase is an essential medicine for childhood ALL. The quality of generic L-asparaginase available in India is a matter of concern. We compared four commonly used generic formulations of L-asparaginase in India. MATERIALS AND METHODS: We conducted a prospective, open-label, randomised trial of four generic formulations of asparaginase for the treatment of patients with newly diagnosed intermediate-risk B-ALL. Patients were randomly assigned in a 1:1:1:1 ratio to receive generic asparaginase at a dose of at 10,000 IU/m 2 on days 9, 12, 15, and 18 of a 35-day cycle (Induction treatment). The primary end points were to determine the difference in the asparaginase activity and asparagine depletion. Historical patients who received L-asparaginase Medac (innovator) served as controls. RESULTS: A total of 48 patients underwent randomization; 12 patients each in the four arms. Failure to achieve predefined activity threshold of 100 IU/L was observed in 9/40 samples of Generic A (22·5%), 23/40 of Generic B (57·5%), and 43/44 (98%) each of Generic C and D. All 27 samples from seven historical patients who were administered Medac had activity > 100 IU/L. The average activity was significantly higher for Genericm A, 154 (70·3, 285·4) IU/L followed by Generic B 84·5(44·2, 289·1) IU/L, Generic C 45(14·4, 58·4) IU/L, and Generic D 20·4(13, 35) IU/L. Only 6 patients had asparaginase activity > 100 IU/L on each of the four occasions (Generic A = 5; Generic B = 1), and none of them developed Anti-Asparaginase Antibodies (AAA). On the other hand, AAA was observed in 12/36 patients who had at least one level < 100 IU/L (P < 0·05): Generic A 3/5, Generic B = 3/9, Generic D (4/11), and Generic C (5/11). CONCLUSION: Generic A and B had better trough asparaginase activity compared to Generic D and C. Overall, generic formulations had lower asparaginase activity which raises serious clinical concerns regarding their quality. Until strict regulatory enforcement improves the quality of these generics, dose adaptive approaches coupled with therapeutic drug monitoring need to be considered.

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

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

Role of Curcumin in Reducing Toxicities Associated With Mucosal Injury Following Melphalan-Based Conditioning in Autologous Transplant Setting.

Mucositis is nearly inevitable following high-dose chemotherapy. Several pro-inflammatory cytokines play a role in pathogenesis of mucositis. Curcumin inhibits inflammatory cytokines through inhibition of nuclear factor kappa-ß. We studied the effects of curcumin on the acute toxicities and inflammatory cytokines following melphalan (200 mg/m2) for autologous hematopoietic stem cell transplantation (HSCT) for myeloma. The control group (first 10 enrolled patients who received standard supportive care) was compared with curcumin group (next 30 patients who received chewable curcumin lozenges, 4 g twice daily from 2 days before melphalan till day +28 along with standard supportive care). The toxicities were recorded as per World Health Organization (WHO) criteria and CTCAE v3.0 as applicable. Cytokine profiling was done in both groups at similar time points. In the curcumin group, there was significant decrease in grade 3/4 vomiting (3% vs 40%, P = 0.01) and total parenteral nutrition use (47% vs 90%, P = 0.026). Grade 3/4 mucositis (43% vs 60%) and diarrhea (33% vs 70%) were also less, but not statistically significant. This coincided with 3.2-fold lower area under the concentration time curve (AUC) of IL-8 from day -3 to day 14 in curcumin group compared with control group (P = 0.039). We conclude that curcumin mitigates toxicities of high-dose melphalan, possibly through IL-8 modulation. Randomized studies are warranted to explore benefits of curcumin in HSCT.

Loco-regional radiosensitizing nanoparticles-in-gel augments head and neck cancer chemoradiotherapy.

The therapeutic gain in loco-regionally advanced unresectable head and neck squamous cell carcinoma (HNSCC) is limited with the traditional use of concurrent chemoradiotherapy (CRT) owing to dose-limiting toxicities of systemic clinical radiosensitizers. Delivery through regional platforms is challenging due to limited drug permeation but allows spatio-temporal control of combinatorial regimens locally to overcome drug resistance. We address these challenges by developing biodegradable gellan- and lipid-based dual nanocarriers-in-ion-triggered porous mucoadhesive hydrogels for enhanced site-specific delivery of clinically relevant radiosensitizers i.e. cisplatin and paclitaxel. Interestingly, the nanoparticle-in-gel prolonged the tumor bioaccumulation of both the chemotherapeutic drugs with reduced systemic absorption, thereby improving in vivo efficacy which was confirmed by PET-CT imaging and safety as compared to systemic commercial formulations approved for HNSCC chemoradiotherapy. The nanoparticles facilitated intracellular radiosensitizer uptake and cell arrest to synergistically enhance radiation-induced DNA nicks and apoptosis. Our findings suggest the clinical potential of the present platform in the loco-regional management of HNSCC requiring curative CRT.

Simultaneous analysis of urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, N'-nitrosonornicotine, and cotinine by liquid chromatography-tandem mass-spectrometry.

Biomarkers of exposure to harmful tobacco constituents are key tools for identifying individuals at risk and developing interventions and tobacco control measures. However, tobacco biomarker studies are scarce in many parts of the world with high prevalence of tobacco use. Our goal was to establish a robust method for simultaneous analysis of urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), N'-nitrosonornicotine (NNN), and cotinine at the Advanced Centre for Treatment, Research and Education in Cancer (ACTREC) in Mumbai, India. These biomarkers are validated measures of exposure to the carcinogenic tobacco nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and NNN and the addictive alkaloid nicotine, respectively. The established method is characterized by excellent accuracy, linearity, and precision, and was successfully applied to the analysis of 15 smokeless tobacco (SLT) users and 15 non-users of tobacco recruited in Mumbai. This is the first report of establishment of such procedure in a laboratory in India, which offers the first in-country capacity for research on tobacco carcinogenesis in Indian SLT users.

Pharmacokinetics of solid lipid Boswellia serrata particles in healthy subjects.

OBJECTIVES: The anti-inflammatory activity of Boswellia serrata extracts (BSE) is well known. BSE comprises boswellic acids (BA) such as 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-boswellic acid (KBA) as major constituents. One of the limitations of BAs is their poor oral bioavailability. The aim of the study was to prepare solid lipid particles of Boswellia serrata extract (SLBSP) to enhance the bioavailability of BAs. METHODS: The pharmacokinetic profile of BAs was studied in 10 healthy human volunteers following a single oral dose of 333 mg of SLBSP. Pharmacokinetic blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h post drug administration. Plasma KBA and AKBA levels were measured using a validated LC-MS/MS method. Pharmacokinetics parameters were estimated using Pheonix WinNonlin (Build 6.4.0.768) software. RESULTS: Ten healthy human volunteers were included and peak plasma concentration was achieved in 1.5 and 2.3 h for AKBA and KBA respectively. Maximum plasma concentration (Cmax) was 8.04 ± 1.67 ng/mL for AKBA and 23.83 ± 4.41 ng/mL for KBA whereas the corresponding area under the concentration-time curve (AUC) was 136.7 ± 56.77 ng/mL*h and 165.7 ± 24.5 ng/mL*h respectively. The elimination half-life (t1/2) of AKBA and KBA was 6.8 ± 3.0 h and 2.45 ± 0.3 h respectively. CONCLUSIONS: The SLBSP formulation of BSE showed enhanced oral bioavailability of BAs compared with historically reported data of unformulated BSE.

Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer.

Lipocalin 2 is a siderophore-binding protein that regulates iron homeostasis. Lipocalin 2 expression is elevated in multiple tumor types; however, the mechanisms that drive tumor progression upon Lipocalin 2 expression remain unclear. When Lipocalin 2 is over-expressed, it leads to resistance to 5-fluorouracil in colon cancer cell lines in vitro and in vivo by inhibiting ferroptosis. Lipocalin 2 inhibits ferroptosis by decreasing intracellular iron levels and stimulating the expression of glutathione peroxidase4 and a component of the cysteine glutamate antiporter, xCT. The increase in xCT levels is dependent on increased levels of ETS1 in Lipocalin 2 over-expressing cells. Inhibiting Lipocalin 2 function with a monoclonal antibody leads to a decrease in chemo-resistance and transformation in vitro, and a decrease in tumor progression and chemo-resistance in xenograft mouse models. Lipocalin 2 and xCT levels exhibit a positive correlation in human tumor samples suggesting that the pathway we have identified in cell lines is operative in human tumor samples. These results indicate that Lipocalin 2 is a potential therapeutic target and that the monoclonal antibody described in our study can serve as the basis for a potential therapeutic in patients who do not respond to chemotherapy.

ADME gene polymorphisms do not influence the pharmacokinetics of docetaxel: Results from a population pharmacokinetic study in Indian cancer patients.

BACKGROUND: Pharmacokinetics (PK) of docetaxel is characterized by high inter-individual variability (IIV). While covariate models that explain the PK variability of docetaxel exist, not much is known about the effects of genetic variations on docetaxel disposition. METHODS: Fifty patients with head and neck or prostate cancer were enrolled of whom two patients withdrew consent before the start of the study. Docetaxel was administered at either 50 or 75 mg/m2 as intravenous infusion over 1 h. One pharmacogenetic sample and a series of PK samples, either intensive (N = 5; 13 samples each) or sparse (N = 43; 6 samples each), were collected from each patient. Docetaxel levels were estimated using a validated HPLC method. Polymorphic loci on the Absorption, Distribution, Metabolism, and Elimination (ADME) genes were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2. RESULTS: Docetaxel PK was well characterized by a three-compartment model. Clearance (Cl) was found to be 18 L/h with an IIV of 45.3%. None of the genetic variants showed significant covariate effect on the Cl of docetaxel. Patients with abnormal alanine aminotransferase (ALT) were found to have 25% lower Cl as compared to patients with normal ALT values. However, the covariate effect could not be established in the final model possibly due to lack of adequate number of patients with abnormal ALT. CONCLUSION: Genetic polymorphisms in the ADME gene do not explain the IIV in PK of docetaxel. However, patients with abnormal liver function might require dose reduction. CLINICAL TRIAL REGISTRATION: Not applicable since participants in this study received treatment that was standard of care.

Effect of body mass index on pharmacokinetics of paclitaxel in patients with early breast cancer.

BACKGROUND: Paclitaxel is dosed according to body surface area (BSA) but there is scant information on actual drug exposure in overweight and obese patients. METHODS: Early breast cancer patients receiving paclitaxel at 175 mg/m2 every 3 weeks, in two BMI groups (normal, 18-24.9 kg/m2 and overweight/obese, ≥25 kg/m2 , respectively), matched for age, serum albumin and bilirubin levels using minimization technique, were included. Sparse pharmacokinetic (PK) sampling was performed at 7 time points from 0 h until 24 h of starting paclitaxel in cycle 1. Paclitaxel concentration was measured using a validated LCMS/MS method. Covariate effect on paclitaxel PK was evaluated by population PK analysis using NONMEM software. RESULTS: Eighteen female patients each were enrolled in normal and overweight groups with mean BMI of 21.62 ± 2.06 and 28.16 ± 2.31 kg/m2 , mean BSA of 1.44 ± 0.11 and 1.69 ± 0.14 m2 and mean paclitaxel dose of 250 ± 18 and 293 ± 21 mg, respectively. Model predicted AUC and dose normalized AUC (mean ±SD) in the normal BMI versus overweight obese groups were 23 ± 11.0 µmol*h/L versus 25.7 ± 13.7 µmol*h/L (two-sample t-test p > 0.05) and 0.08 ± 0.04 (µmol*h/L)/ µmol versus 0.08 ± 0.04 (µmol*h/L)/ µmol (2-sample t-test p > 0.05), respectively. No significant correlation was observed between BMI and standardized dose normalized AUC (Pearson's correlation coefficient, -0.009; p > 0.05). CONCLUSION: When dosed according to BSA calculated using actual body weight there is no significant difference in paclitaxel exposure between normal and overweight women. Using alternative descriptors of weight to calculate BSA could lead to under-dosing of this drug. TRIAL REGISTRATION: This study is registered in the Clinical Trials Registry of India CTRI/2015/09/006193.

Pharmacokinetics of solid lipid Boswellia serrata particles in healthy subjects.

OBJECTIVES: The anti-inflammatory activity of Boswellia serrata extracts (BSE) is well known. BSE comprises boswellic acids (BA) such as 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-boswellic acid (KBA) as major constituents. One of the limitations of BAs is their poor oral bioavailability. The aim of the study was to prepare solid lipid particles of Boswellia serrata extract (SLBSP) to enhance the bioavailability of BAs. METHODS: The pharmacokinetic profile of BAs was studied in 10 healthy human volunteers following a single oral dose of 333 mg of SLBSP. Pharmacokinetic blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h post drug administration. Plasma KBA and AKBA levels were measured using a validated LC-MS/MS method. Pharmacokinetics parameters were estimated using Pheonix WinNonlin (Build 6.4.0.768) software. RESULTS: Ten healthy human volunteers were included and peak plasma concentration was achieved in 1.5 and 2.3 h for AKBA and KBA respectively. Maximum plasma concentration (C max) was 8.04 ± 1.67 ng/mL for AKBA and 23.83 ± 4.41 ng/mL for KBA whereas the corresponding area under the concentration-time curve (AUC) was 136.7 ± 56.77 ng/mL*h and 165.7 ± 24.5 ng/mL*h respectively. The elimination half-life (t 1/2) of AKBA and KBA was 6.8 ± 3.0 h and 2.45 ± 0.3 h respectively. CONCLUSIONS: The SLBSP formulation of BSE showed enhanced oral bioavailability of BAs compared with historically reported data of unformulated BSE.

Safety and CSF distribution of high-dose erlotinib and gefitinib in patients of non-small cell lung cancer (NSCLC) with brain metastases.

PURPOSE: Patients of non-small cell lung cancer (NSCLC) with brain metastases have limited treatment options. High-dose erlotinib (HDE) and gefitinib (HDG) have been tried in the past. This study investigates the cerebrospinal fluid (CSF) disposition and safety of both, high-dose erlotinib and gefitinib regimens. METHODS: Eleven and nine patients were treated with erlotinib and gefitinib, respectively. All patients received 1 week of standard dose of erlotinib (150 mg OD) or gefitinib (250 mg OD), followed by the high dose (1500 mg weekly for erlotinib and 1250 mg OD for gefitinib) from day 8. Blood and CSF samples were collected on days 7 and 15, 4 h after the morning dose and drug levels determined using LC-MS/MS. Adverse events were documented as per CTCAE 4.03 till day 15. RESULTS: Pulsatile HDE and daily HDG resulted in 1.4- and 1.9-fold increase in CSF levels, respectively. A constant 2% CSF penetration rate was observed across both doses of erlotinib, while for gefitinib the penetration rate for high dose was half that of the standard dose suggesting a nonlinear disposition. Three patients on HDE treatment discontinued treatment after the first dose due to intolerable toxicities, whereas HDG was better tolerated with no treatment discontinuations. Since CSF disposition of gefitinib followed saturable kinetics, a lower dose of 750 mg was found to achieve CSF concentrations comparable to that of the 1250 mg dose. CONCLUSIONS: HDG was better tolerated than HDE. CSF disposition of gefitinib was found to be saturable at a higher dose. Based on these findings, the dose of 750 mg OD should be considered for further evaluation in this setting.

Tuning the pharmacokinetics and efficacy of irinotecan (IRI) loaded gelatin nanoparticles through folate conjugation.

Gelatin based nanocarriers have major limitation of shorter circulation half-life (t1/2). Present study addressed this issue by conjugating gelatin with folate followed by nanoprecipitation in presence of polysorbate 80 to form folate attached gelatin nanoparticles (GNP-F). The folic acid was conjugated with gelatin through the formation of amide linkage with a maximum conjugation yield of ~69%. Cryo-SEM analysis indicated that unconjugated gelatin nanoparticles (GNP) and GNP-F were spherical of nearly identical size of ~200 nm. The irinotecan (IRI)-loading efficiency estimated for IRI-GNP and IRI-GNP-F was 6.6 ± 0.42% and 11.2 ± 0.73% respectively and both formulations showed faster release of IRI at acidic pH (~5) than at physiological pH (~7). Further IRI-GNP-F demonstrated significantly higher cytotoxicity in folate receptor (FR)-positive HeLa cells than the unconjugated IRI-GNP nanoparticles confirming active targeting. Subsequently the antitumor activity of above formulations in FR-positive fibrosarcoma (syngeneic) tumor-bearing mice followed the order of IRI-GNP-F > IRI-GNP > free IRI. The pharmacokinetic evaluation of IRI-GNP and IRI-GNP-F revealed that encapsulation of IRI within GNP without folate improved its plasma maximum concentration (Cmax). However, folate conjugation of GNP remarkably improved the t1/2 of IRI. Taken together, folate as a targeting ligand modulates the pharmacokinetic property of IRI loaded GNP to favor active verses passive targeting.

A Limited Sampling Strategy for Therapeutic Drug Monitoring of Mycophenolate Mofetil for Prophylaxis of Acute Graft-Versus-Host Disease in Allogeneic Stem Cell Transplantation.

A universally accepted strategy for therapeutic drug monitoring (TDM) of mycophenolate mofetil (MMF) in the prevention of acute graft-versus-host disease (aGVHD) in allogenic hematopoietic stem cell transplantation (alloHSCT) does not exist. We explored the feasibility of developing a limited sampling strategy (LSS) for TDM of MMF in this setting. Patients undergoing alloHSCT received standard MMF-cyclosporine prophylaxis, with MMF administered twice daily (BD) for matched transplant recipients or thrice daily (TID) in haploidentical transplantation. Intensive blood sampling was carried out on day 7 and area under the concentration-time curve (AUC) of mycophenolic acid (MPA), the active metabolite, was estimated using noncompartmental analysis. The ability of MPA exposure defined by AUC0-12 to discriminate between responders (patients who did not develop GVHD) and nonresponders (patients who developed GVHD) was determined by receiver operating characteristic curve analysis. Patients were divided into training and validation sets within BD and TID groups. Mathematical equations were developed from the training set to predict AUC0-12 from an abbreviated AUC involving a limited number of sampling points. The equations were validated in the validation set by comparing the MPA AUC0-12 predicted from LSS with the observed AUC0-12. It was observed that patients with AUC0-12 ≤18.99 mg*h/L had a higher risk of developing aGVHD [odds ratio (OR) = 2.63 (1.17 to 5.87), P = 0.06]. The benefit was more in matched transplant recipients [OR = 3.5 (1.30 to 9.49), P = 0.05] as compared to haploindentical transplant [OR = 2.8 (0.49 to 15.91), P = NS]. Using the mathematical equations, the observed AUC0-12 was predicted with 92.31% accuracy in the BD subset and 100% accuracy in the TID subset for a combined accuracy of 94.76%. A set of just three samples that constituted the abbreviated AUC1-4 was used to develop the predictive models. The LSS could be employed for the therapeutic monitoring of MMF particularly in patients undergoing matched hematopoietic stem cell transplantation.

Objective assessment of intraoperative tumor fluorescence reveals biological heterogeneity within glioblastomas: a biometric study.

PURPOSE: Heterogeneity within GBMs and variability of visualized fluorescence combine to confer practical limitations to the technique of optical imaging. A biometric analysis was planned to objectively ascertain and analyse this phenomenon METHODS: 25 adult glioblastoma subjects undergoing resection were prospectively accrued. Biopsies were taken from various parts of the tumor and safe peritumoral zones. White light (WL) and visualized fluorescence was subjectively recorded. Corresponding histopathology [coalescent (C) or infiltrating (I) tumor] and protoporphyrin-IX (PPIX) levels were assayed. RESULTS: WL was very sensitive for detecting tumor. SF was more specific and had high positive predictive value for detecting tumor. WF on the other hand had a poor discriminatory efficacy. Mean PPIX levels were 3.0, 2.01 and 0.16 for SF, WF, and NF respectively. WF had a wide variable range of PPIX levels. Within the coalescent tumor areas, there was a variable distribution of fluorescence (both subjective as well as objective PPIX levels) with only 54% samples showing SF and high PPIX. In seven cases this discordance was noted within the same tumor (biological heterogeneity). CONCLUSIONS: Fluorescence may miss important tumor areas even if objective assessment is used. Histologically similar tumor areas may exhibit contrasting fluorescence properties, a phenomenon which needs further investigation and elucidation of underlying mechanisms which could potentially be manipulated to optimize the utility of fluorescence guidance.

An HPLC method for simultaneous quantification of sunitinib and its active metabolite, SU12662, using hydrophilic interaction chromatography principle.

Aim: To develop a sensitive HPLC method for the quantitation of sunitinib (SU) and its active metabolite N-desethyl-sunitinib (SU12662) in human plasma. Materials & methods: The analytes were extracted from 500 µl of plasma using liquid-liquid extraction followed by protein precipitation. Chromatographic separation of two analytes and internal standard, vandetenib, was achieved on a hydrophilic interaction liquid chromatography analytical column using a gradient program. Calibration curves were linear over the range of 10-250 ng/ml for both SU and SU12662. The method was validated according to the US FDA guidelines for bioanalytical methods. Accuracy of the method at 10 ng/ml for SU and SU12662 was 8.7 and 6.7%, respectively, and precision was 10.18% and 17.3%, respectively. Conclusion: This method allows a specific, sensitive and reliable determination of SU and SU12662 in human plasma in a single analytical run which makes it useful for therapeutic drug monitoring.

Clinical pharmacokinetics of 3-h extended infusion of meropenem in adult patients with severe sepsis and septic shock: implications for empirical therapy against Gram-negative bacteria.

BACKGROUND: Optimal anti-bacterial activity of meropenem requires maintenance of its plasma concentration (Cp) above the minimum inhibitory concentration (MIC) of the pathogen for at least 40% of the dosing interval (fT > MIC > 40). We aimed to determine whether a 3-h extended infusion (EI) of meropenem achieves fT > MIC > 40 on the first and third days of therapy in patients with severe sepsis or septic shock. We also simulated the performance of the EI with respect to other pharmacokinetic (PK) targets such as fT > 4 × MIC > 40, fT > MIC = 100, and fT > 4 × MIC = 100. METHODS: Arterial blood samples of 25 adults with severe sepsis or septic shock receiving meropenem 1000 mg as a 3-h EI eight hourly (Q8H) were obtained at various intervals during and after the first and seventh doses. Plasma meropenem concentrations were determined using a reverse-phase high-performance liquid chromatography assay, followed by modeling and simulation of PK data. European Committee on Antimicrobial Susceptibility Testing (EUCAST) definitions of MIC breakpoints for sensitive and resistant Gram-negative bacteria were used. RESULTS: A 3-h EI of meropenem 1000 mg Q8H achieved fT > 2 µg/mL > 40 on the first and third days, providing activity against sensitive strains of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. However, it failed to achieve fT > 4 µg/mL > 40 to provide activity against strains susceptible to increased exposure in 33.3 and 39.1% patients on the first and the third days, respectively. Modeling and simulation showed that a bolus dose of 500 mg followed by 3-h EI of meropenem 1500 mg Q8H will achieve this target. A bolus of 500 mg followed by an infusion of 2000 mg would be required to achieve fT > 8 µg > 40. Targets of fT > 4 µg/mL = 100 and fT > 8 µg/mL = 100 may be achievable in two-thirds of patients by increasing the frequency of dosing to six hourly (Q6H). CONCLUSIONS: In patients with severe sepsis or septic shock, EI of 1000 mg of meropenem over 3 h administered Q8H is inadequate to provide activity (fT > 4 µg/mL > 40) against strains susceptible to increased exposure, which requires a bolus of 500 mg followed by EI of 1500 mg Q8H. While fT > 8 µg/mL > 40 require escalation of EI dose, fT > 4 µg/mL = 100 and fT > 8 µg/mL = 100 require escalation of both EI dose and frequency.