Phase 0 trials/ Intra-Target-Microdosing (ITM) and the lung: a review.

The COVID-19 pandemic has highlighted the importance of efficient drug discovery in respiratory disease. The traditional set up of clinical trials is expensive and allows for significant attrition of new drugs, many of which undergo extensive safety testing before being abandoned for lack of efficacy. Phase 0 trials, named as they sit between pre-clinical research and phase I, allow for the testing of sub-clinical microdoses in humans to gather early pharmacokinetic (PK), pharmacodynamic (PD) and mechanistic data, before deciding on which drugs to advance further. This early data can improve the efficiency and cost effectiveness of drug development and reduce the extent of animal testing. Phase 0 trials traditionally have utilised sub-therapeutic microdoses of compounds administered intravenously with readouts focusing on PK - measured using highly sensitive methods such as accelerator mass spectrometry (AMS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) of peripheral blood, as well as whole-body positron emission tomography (PET). Mathematical models allow for extrapolation of this PK data to support the further testing of larger, systemically effective doses. However, this extrapolation method is limited at providing robust PD or target engagement/ mode of action data. Using an Intra-Target Microdosing (ITM) approach, a small compartment of the body (about 1% or less) is exposed to potentially clinically active local concentrations. This allows for the collection of PD data, evidence of target cell engagement, as well as the opportunity to extrapolate systemic PK and PD data. This approach has the potential within the pulmonary system for the study and rapid and cost-effective development of new and repurposed drugs.

Experiences of microdosing psychedelics in an attempt to support wellbeing and mental health.

BACKGROUND: Microdosing psychedelic drugs is a growing phenomenon, but little is known about the experiences surrounding this. Research broadly suggests that people may use psychedelics in an attempt to self-medicate for mental health and wellbeing. However, the precise details, rationale and meaning of such attempts remains unclear, and would benefit from clarification, using tailored experiential methods. This research therefore aimed to explore the way that users make sense of microdosing psychedelics, with a particular focus on the experience of any perceived mental health or wellbeing changes. METHOD: Participants were recruited via websites and online forums. An internet text-based, semi-structured interview was conducted anonymously with 13 participants regarding their experiences of microdosing psychedelic drugs. Interpretive Phenomenological Analysis was used to analyse the transcripts. RESULTS: Three superordinate themes were identified through the interviews: 1) Seeking a solution: Agency and rationale; 2) Microdosers as scientists; 3) Catalysing desirable and beneficial effects. CONCLUSIONS: All participants approached microdosing methodically and with purpose. Participants reported that they had experienced beneficial effects of microdosing on their mental health, alongside cognitive, physical and social changes. By microdosing, participants reported that they had supported their own mental health and wellbeing, with microdosing described as a catalyst to achieving their aims in this area. This study provided additional knowledge and understanding of the experience, rationale and personal meaning of the microdosing phenomenon which can be used to inform future investigations in the areas of psychedelic use and mental health.

Legal Limitations Associated with Microdosing Buprenorphine.

Background: Opioid overdose deaths in the U.S. continue to increase, largely due to the prevalence of fentanyl, a very powerful opioid, in the illicit drug supply. Buprenorphine treatment is effective for treating opioid use disorder, but it can be challenging for clinicians to introduce buprenorphine treatment to people who use fentanyl due to risks of precipitated withdrawal. Induction could be facilitated through a buprenorphine microdosing approach called "the Bernese method." Objective: In this commentary, we describe how federal laws inadvertently limit optimal use of the Bernese method and how federal laws could be reformed to facilitate use of the Bernese method. Results: The Bernese method requires patients to continue using the opioid of misuse (e.g., fentanyl) for seven to ten days while receiving very low doses of buprenorphine. Under federal law, the typical office-based buprenorphine prescriber can neither prescribe nor administer fentanyl short-term for buprenorphine induction purposes, essentially forcing patients to continue to temporarily obtain fentanyl via the illicit market. Conclusion: The federal government has already indicated its support for increasing buprenorphine access. We argue that the government should permit short-term dispensing of fentanyl to office-based patients undergoing buprenorphine induction.

Carbon-13 labeling of ibrutinib for human microdosing.

Ibrutinib is an oral medication for the treatment of B cell malignancies. During its clinical development, a stable isotopologue of ibrutinib was required for the assessment of the drug's absolute oral bioavailability via intravenous microdosing. The following work describes a 10-step, gram-scale production of carbon-13 labeled ibrutinib from [13 C6 ]phenol (13 C6 , 99%) in 31% overall yield with >99% chemical purity and >99% enantiomeric excess (ee), suitable for intravenous microdosing in humans.

Microdosing Sprint Distribution as an Alternative to Achieve Better Sprint Performance in Field Hockey Players.

Introduction: The implementation of optimal sprint training volume is a relevant component of team sport performance. This study aimed to compare the efficiency and effectiveness of two different configurations of within-season training load distribution on sprint performance over 6 weeks. Methods: Twenty male professional FH players participated in the study. Players were conveniently assigned to two groups: the experimental group (MG; n = 11; applying the microdosing training methodology) and the control group (TG; n = 9; traditional training, with players being selected by the national team). Sprint performance was evaluated through 20 m sprint time (T20) m and horizontal force−velocity profile (HFVP) tests before (Pre) and after (Post) intervention. Both measurements were separated by a period of 6 weeks. The specific sprint training program was performed for each group (for vs. two weekly sessions for MG and TG, respectively) attempting to influence the full spectrum of the F-V relationship. Results: Conditional demands analysis (matches and training sessions) showed no significant differences between the groups during the intervention period (p > 0.05). No significant between-group differences were found at Pre or Post for any sprint-related performance (p > 0.05). Nevertheless, intra-group analysis revealed significant differences in F0, Pmax, RFmean at 10 m and every achieved time for distances ranging from 5 to 25 m for MG (p < 0.05). Such changes in mechanical capabilities and sprint performance were characterized by an increase in stride length and a decrease in stride frequency during the maximal velocity phase (p < 0.05). Conclusion: Implementing strategies such as microdosed training load distribution appears to be an effective and efficient alternative for sprint training in team sports such as hockey.

Micro-dosing of powders into capsules using a new automated micro-dosing system: effect of powder characteristics and operating conditions on the filling of 0.5 mg-100 mg weights.

OBJECTIVE: To demonstrate the applicability of a novel micro-dosing system for precisely filling low powder doses (down to a few mg) into capsules along with weighing the filled powder mass accurately. METHODS: Ten commonly used pharmaceutical powders, ranging from cohesive to free-flowing, were selected and filled at three target fill weights (0.5, 1, and 10 mg), to investigate the effect of distinct powder properties on the filling performance. The fill weight and variability, filling speed and yield (% and number of conforming capsules out of all capsules collected), as well as the system's long-term performance were assessed. RESULTS: The filling accuracy was found to be good for all investigated powders. In particular, the results demonstrate that the tested powders, including the challenging cohesive ones, could be dosed at standard deviations within 0.23 mg at a 10 mg target weight, within 0.07 mg at a 1 mg target weight, and within 0.05 mg at a 0.5 mg target weight. In all cases, free-flowing powders showed lower standard deviations. Intermediate and cohesive powders had slightly higher standard deviations but were still within an acceptable range. CONCLUSION: The study shows the suitability of the tested micro-dosing system for filling low powder doses into capsules, which is of particular importance for dosing active pharmaceutical ingredients (APIs) directly in capsules, i.e. an API-in-capsule (AIC) approach for clinical trials (often in conjunction with highly potent APIs), and for low-dose powder filling for inhalation applications.

Repeated low doses of LSD in healthy adults: A placebo-controlled, dose-response study.

The resurgence of interest in using psychedelic drugs, including lysergic acid diethylamide (LSD), in psychiatry has drawn attention to the medically unsupervised practice of 'microdosing'. Thousands of users claim that very low doses of LSD, taken at 3-4-day intervals, improve mood and cognitive function., However, few controlled studies have described the effects of the drug when taken in this way. Here, in a double-blind controlled study, we studied the effects of four repeated doses of LSD tartrate (13 or 26 µg) or placebo, administered to healthy adults at 3-4 day intervals, on mood, cognitive performance and responses to emotional tasks. Participants were randomly assigned to one of three drug conditions: placebo (N = 18), 13 µg LSD (N = 19), or 26 µg LSD (N = 19). They attended four 5-hour drug-administration sessions separated by 3-4 days, followed by a drug-free follow-up session 3-4 days after the last session. LSD (26 µg) produced modest subjective effects including increased ratings of 'feeling a drug effect' and both stimulant-like and LSD-like effects, but the drug did not improve mood or affect performance on psychomotor or most emotional tasks. No residual effects were detected on mood or task performance on the drug-free follow-up session. We conclude that within the context of a controlled setting and a limited number of administrations, repeated low doses of LSD are safe, but produce negligible changes in mood or cognition in healthy volunteers.

Highly sensitive quantification of pemetrexed in human plasma using UPLC-MS/MS to support microdosing studies.

Pemetrexed is an antifolate drug approved for the treatment of non-small-cell lung cancer and mesothelioma. Assessing pemetrexed pharmacokinetics after administration of a microdose (100 µg) may facilitate drug-drug interaction and dose individualization studies with cytotoxic drugs, without causing harm to patients. Therefore, a highly sensitive bioanalytical assay is required. A reversed-phase ultra-high performance liquid chromatography method was developed to determine pemetrexed concentrations in human ethylenediaminetetraacetic acid-plasma after microdosing. [13 C5 ]-Pemetrexed was used as the internal standard. The sample preparation involved solid-phase extraction from plasma. Detection was performed using MS/MS in a total run time of 9.5 min. The assay was validated over the concentration range of 0.0250-25.0 µg/L pemetrexed. The average accuracies for the assay in plasma were 96.5 and 96.5%, and the within-day and between-day precision in coefficients of variations was <8.8%. Extraction recovery was 59 ± 1 and 55 ± 5% for pemetrexed and its internal standard. Processed plasma samples were stable for 2 days in a cooled autosampler at 10°C. The assay was successfully applied in a pharmacokinetic curve, which was obtained as a part of an ongoing clinical microdosing study.

Ultra-Low Energy Cycled Burst Spinal Cord Stimulation Yields Robust Outcomes in Pain, Function, and Affective Domains: A Subanalysis From Two Prospective, Multicenter, International Clinical Trials.

INTRODUCTION: DeRidder's burst stimulation design has become a key spinal cord stimulation (SCS) waveform because it reduces the intensity of pain as well as its associated emotional distress. The brain pathways underlying these outcomes may also allow for the effects of stimulation to carry over after stimulation is turned off, making it amenable to intermittent application. Here, the utility of intermittently cycled burst was evaluated using data from two large real-world prospective studies (TRIUMPH, REALITY). MATERIALS AND METHODS: Subjects used intermittent dosing in a 1:3 ratio (30 sec on, 90 sec off; N = 100) in TRIUMPH and 1:12 ratio in REALITY (30-sec on, 360-sec off; N = 95) for six months. Pain intensity (0-10 numeric rating scale), pain-related emotions on the pain catastrophizing scale (PCS), and physical function on PROMIS questionnaires were compared with preimplant baseline ratings and by group. RESULTS: In both groups, mean pain intensity decreased by nearly 50% relative to baseline, PCS scores significantly decreased, and physical function improved. Importantly, no differences between the 1:3 and 1:12 groups were identified. A high proportion, 80% and 77% of the 1:3 and 1:12 groups, respectively, were considered responders on a multiple measures. No adverse events were associated with intermittent stimulation. DISCUSSION: Intermittent cycling of burst SCS lowers the overall electric charge delivered to the spinal cord and preserves battery consumption, without compromising pain relief and associated symptoms.

Midazolam microdosing applied in early clinical development for drug-drug interaction assessment.

AIMS: We aimed to incorporate a pharmacologically inactive midazolam microdose into early clinical studies for the assessment of CYP3A drug-drug interaction liability. METHODS: Three early clinical studies were conducted with substances (Compounds A, B and C) which gave positive CYP3A perpetrator signals in vitro. A 75 µg dose of midazolam was administered alone (baseline CYP3A activity) followed by administration with the highest dose groups tested for each compound on Day 1/3 and Day 14 or Day 17. Midazolam exposure (AUC0-∞ , Cmax ) during administration with the test substances was compared to baseline data via an analysis of variance on log-transformed data. Partial AUC2-4 ratios were also compared to AUC0-∞ ratios using linear regression on log-transformed data. RESULTS: Test compound Cmax values exceeded relevant thresholds for drug-drug interaction liability. Midazolam concentrations were quantifiable over the full profiles for all subjects in all studies. Point estimates of the midazolam AUC0-∞ gMean ratios ranged from 108.3 to 127.1% for Compound A, from 93.3 to 114.5% for Compound B, and from 92.0 to 96.7% for the two highest dose groups of Compound C. Cmax gMean ratios were in the same range. Thus, no relevant drug-drug interactions were evident, based on the results of midazolam microdosing. AUC2-4 ratios from these studies were comparable to the AUC0-∞ ratios. CONCLUSION: Midazolam microdosing incorporated into early clinical studies is a feasible tool for reducing dedicated drug-drug interaction studies, meaning reduced subject burden. Limited sampling could further reduce subject burden, costs and needed resources.

Treating Chronic Pain with Buprenorphine-The Practical Guide.

OPINION STATEMENT: Buprenorphine has unique and favorable pharmacological properties that make it useful in a variety of clinical scenarios. It has been recommended to consider buprenorphine first-line opioid for chronic pain, especially in the elderly as it may be associated with less cognitive impairment, falls, sexual dysfunction, and sarcopenia when compared with schedule II opioids. It may be useful in patients with comorbid substance use disorder or non-medical opioid use, as there is less risk of misuse, euphoria and it may improve mood. When used to treat opioid use disorder, the training and waiver was recently waived for licensed practitioners with a DEA and any provider may prescribe buprenorphine. For many reasons outlined in this article, the popularity of using buprenorphine for analgesia continues to grow and a practitioner should consider this as an excellent and safe option for chronic pain.

Rapid buprenorphine microdosing for opioid use disorder in a hospitalized patient receiving very high doses of full agonist opioids for acute pain management: Titration, implementation barriers, and strategies to overcomes.

Background: Conventional buprenorphine inductions for OUD are clinically useful but require patients to experience mild to moderate opioid withdrawal symptoms to avoid precipitated withdrawal. This may be intolerable/unreasonable for some, which may have precluded successful buprenorphine treatment in the past. Microdosing buprenorphine, allowing for full agonist opioid overlap, has emerged as a clinically useful strategy for those unable to complete conventional buprenorphine induction. However, many questions remain such as preclusions regarding the amount of full agonist opioid overlap, speed of buprenorphine microdose titration, and overcoming implementation barriers in U.S. hospitals. Case presentation: A female between the ages of 30 and 40 with severe OUD admitted to the hospital for IDU-related osteomyelitis wished to begin buprenorphine for OUD. Her hospitalization was subject to premature discharge at any time due to competing interests of potential foreclosure on her home, so buprenorphine needed to be started rapidly for safety and improved outcomes. Due to her significant acute pain requirements managed with full agonist opioids, it was unreasonable to consider conventional buprenorphine induction. Buprenorphine microdose strategy was employed at more rapid titration and previously described in the literature, starting at 1 mg TDD on day 1, 3 mg TDD on day 2, and 8 mg TDD on day 3 with full agonist opioid overlap starting at 1,944 MME tapered down to 473 MME. The patient prematurely left the hospital, at which time buprenorphine 8 mg TDD was held at this dose for days 3-8 while full agonist opioid was tapered from 473 MME to 117 MME. BUP was then further titrated to 8 mg TID. This patient tolerated buprenorphine microdosing well, without any treatment-emergent opioid symptoms or worsening of baseline symptoms. Discussion: This case demonstrates the success of buprenorphine microdose induction despite very high doses of full agonist opioid overlap and demonstrates the ability to titrate buprenorphine microdoses faster than originally described. Strategies to overcoming implementation barriers are also discussed.

Determination of the absolute bioavailability of oral imatinib using a stable isotopically labeled intravenous imatinib-d8 microdose.

PURPOSE: The aim of this study was to ascertain whether the absolute bioavailability of oral imatinib (Glivec®) during steady state plasma pharmacokinetics in cancer patients could be determined through a concomitant intravenous administration of a single 100 µg microdose of deuterium labeled imatinib (imatinib-d8). Secondly, the usefulness of liquid chromatography-tandem mass spectrometry (LC-MS/MS) was investigated for simultaneous analysis of orally and intravenously administered imatinib. METHODS: Included patients were on a stable daily dose of 400 mg oral imatinib prior to study participation. On day 1, patients received a 100 µg intravenous imatinib-d8 microdose 2.5 h after intake of the oral dose. Plasma samples were collected for 48 h. Imatinib and imatinib-d8 concentrations were simultaneously quantified using a validated LC-MS/MS assay. The absolute bioavailability was calculated by comparing the dose-normalized exposure with unlabeled and stable isotopically labeled imatinib in plasma. RESULTS: A total of six patients were enrolled. All patients had a history of gastrointestinal stromal tumors (GIST). The median absolute bioavailability of oral imatinib at steady state was 76% (range 44-106%). Imatinib and imatinib-d8 plasma concentrations were quantified in all collected plasma samples, with no samples below the limit of quantification for imatinib-d8. CONCLUSION: The absolute bioavailability of imatinib was successfully estimated at steady state plasma pharmacokinetics using the stable isotopically labeled microdose trial design. This study exhibits the use of a stable isotopically labeled intravenous microdose to determine the absolute bioavailability of an oral anticancer agent in patients with LC-MS/MS as the analytical tool.

Toxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing.

Benzo[a]pyrene (BaP), is a known human carcinogen (International Agency for Research on Cancer (IARC) class 1). The remarkable sensitivity (zepto-attomole 14C in biological samples) of accelerator mass spectrometry (AMS) makes possible, with de minimus risk, pharmacokinetic (PK) analysis following [14C]-BaP micro-dosing of humans. A 46 ng (5 nCi) dose was given thrice to 5 volunteers with minimum 2 weeks between dosing and plasma collected over 72 h. [14C]-BaPeq PK analysis gave plasma Tmax and Cmax values of 1.25 h and 29-82 fg/mL, respectively. PK parameters were assessed by non- compartment and compartment models. Intervals between dosing ranged from 20 to 420 days and had little impact on intra-individual variation. DNA, extracted from peripheral blood mononuclear cells (PBMCs) of 4 volunteers, showed measurable levels (LOD ~ 0.5 adducts/1011 nucleotides) in two individuals 2-3 h post-dose, approximately three orders of magnitude lower than smokers or occupationally-exposed individuals. Little or no DNA binding was detectable at 48-72 h. In volunteers the allelic variants CYP1B1*1/*⁎1, *1/*3 or *3/*3 and GSTM1*0/0 or *1 had no impact on [14C]-BaPeq PK or DNA adduction with this very limited sample. Plasma metabolites over 72 h from two individuals (one CYP1B1*1/*1 and one CYP1B1*3/*3) were analyzed by UPLC-AMS. In both individuals, parent [14C]-BaP was a minor constituent even at the earliest time points and metabolite profiles markedly distinct. AMS, coupled with UPLC, could be used in humans to enhance the accuracy of pharmacokinetics, toxicokinetics and risk assessment of environmental carcinogens.

Simultaneous phenotyping of CYP2E1 and CYP3A using oral chlorzoxazone and midazolam microdoses.

AIMS: Chlorzoxazone is the paradigm marker substrate for CYP2E1 phenotyping in vivo. Because at the commonly used milligram doses (250-750 mg) chlorzoxazone acts as an inhibitor of the CYP3A4/5 marker substrate midazolam, previous attempts failed to combine both drugs in a common phenotyping cocktail. Microdosing chlorzoxazone could circumvent this problem. METHOD: We enrolled 12 healthy volunteers in a trial investigating the dose-exposure relationship of single ascending chlorzoxazone oral doses over a 10,000-fold range (0.05-500 mg) and assessed the effect of 0.1 and 500 mg of chlorzoxazone on oral midazolam pharmacokinetics (0.003 mg). RESULTS: Chlorzoxazone area under the concentration-time curve was dose-linear in the dose range between 0.05 and 5 mg. A nonlinear increase occurred with doses ≥50 mg, probably due to saturated presystemic metabolic elimination. While midazolam area under the concentration-time curve increased 2-fold when coadministered with 500 mg of chlorzoxazone, there was no pharmacokinetic interaction between chlorzoxazone and midazolam microdoses. CONCLUSION: The chlorzoxazone microdose did not interact with the CYP3A marker substrate midazolam, enabling the simultaneous administration in a phenotyping cocktail. This microdose assay is now ready to be further validated and tested as a phenotyping procedure assessing the impact of induction and inhibition of CYP2E1 on chlorzoxazone microdose pharmacokinetics.

Psychedelic microdosing benefits and challenges: an empirical codebook.

BACKGROUND: Microdosing psychedelics is the practice of consuming very low, sub-hallucinogenic doses of a psychedelic substance, such as lysergic acid diethylamide (LSD) or psilocybin-containing mushrooms. According to media reports, microdosing has grown in popularity, yet the scientific literature contains minimal research on this practice. There has been limited reporting on adverse events associated with microdosing, and the experiences of microdosers in community samples have not been categorized. METHODS: In the present study, we develop a codebook of microdosing benefits and challenges (MDBC) based on the qualitative reports of a real-world sample of 278 microdosers. RESULTS: We describe novel findings, both in terms of beneficial outcomes, such as improved mood (26.6%) and focus (14.8%), and in terms of challenging outcomes, such as physiological discomfort (18.0%) and increased anxiety (6.7%). We also show parallels between benefits and drawbacks and discuss the implications of these results. We probe for substance-dependent differences, finding that psilocybin-only users report the benefits of microdosing were more important than other users report. CONCLUSIONS: These mixed-methods results help summarize and frame the experiences reported by an active microdosing community as high-potential avenues for future scientific research. The MDBC taxonomy reported here informs future research, leveraging participant reports to distil the highest-potential intervention targets so research funding can be efficiently allocated. Microdosing research complements the full-dose literature as clinical treatments are developed and neuropharmacological mechanisms are sought. This framework aims to inform researchers and clinicians as experimental microdosing research begins in earnest in the years to come.

Twenty percent better with 20 micrograms? A qualitative study of psychedelic microdosing self-rapports and discussions on YouTube.

BACKGROUND: Psychedelic microdosing is the trending practice of using tiny repeated doses of psychedelic substances to facilitate a range of supposed benefits. With only a few published studies to date, the subject is still under-researched, and more knowledge is warranted. Social media and internet discussion forums have played a vital role in the growing visibility of the microdosing phenomenon, and the present study utilized YouTube contents to improve comprehension of the microdosing practice as well as the social interactions and discussions around microdosing. METHODS: Microdosing self-disclosure in YouTube videos and their following comments were qualitatively analyzed by inductive thematic analysis. Various software was utilized to enable gathering and sorting relevant data. RESULTS: Microdosing of psychedelic substances, primarily LSD and psilocybin, was used for therapeutic and enhancement purposes, and predominantly beneficial effects were reported. Many different applications and outcomes were discussed, and therapeutic effects for depression appeared especially noteworthy. Intentions for use were recognized as an influencing factor for the progression and outcomes of microdosing. The function of social interactions was mainly to discuss views on the microdosing phenomenon, strategies for optimal results, minimize risks, and share emotional support. CONCLUSIONS: Potentially, microdosing could provide some of the same benefits (for certain conditions) as full-dose interventions with less risk of adverse reactions related to the sometimes intense experiences of higher doses. Microdosing may well also mean additional benefits, as well as risks, through the repeated exposure over extended periods.

A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer.

The platinum-based drugs cisplatin, carboplatin and oxaliplatin are often used for chemotherapy, but drug resistance is common. The prediction of resistance to these drugs via genomics is a challenging problem since hundreds of genes are involved. A possible alternative is to use mass spectrometry to determine the propensity for cells to form drug-DNA adducts-the pharmacodynamic drug-target complex for this class of drugs. The feasibility of predictive diagnostic microdosing was assessed in non-small cell lung cancer (NSCLC) cell culture and a pilot clinical trial. Accelerator mass spectrometry (AMS) was used to quantify [14 C]carboplatin-DNA monoadduct levels in the cell lines induced by microdoses and therapeutic doses of carboplatin, followed by correlation with carboplatin IC50 values for each cell line. The adduct levels in cell culture experiments were linearly proportional to dose (R2 = 0.95, p < 0.0001) and correlated with IC50 across all cell lines for microdose and therapeutically relevant carboplatin concentrations (p = 0.02 and p = 0.01, respectively). A pilot microdosing clinical trial was conducted to define protocols and gather preliminary data. Plasma pharmacokinetics (PK) and [14 C]carboplatin-DNA adducts in white blood cells and tumor tissues from six NSCLC patients were quantified via AMS. The blood plasma half-life of [14 C]carboplatin administered as a microdose was consistent with the known PK of therapeutic dosing. The optimal [14 C]carboplatin formulation for the microdose was 107 dpm/kg of body weight and 1% of the therapeutic dose for the total mass of carboplatin. No microdose-associated toxicity was observed in the patients. Additional accruals are required to significantly correlate adduct levels with response.

Fluorescence guided surgery and tracer-dose, fact or fiction?

INTRODUCTION: Fluorescence guidance is an upcoming methodology to improve surgical accuracy. Challenging herein is the identification of the minimum dose at which the tracer can be detected with a clinical-grade fluorescence camera. Using a hybrid tracer such as indocyanine green (ICG)-(99m)Tc-nanocolloid, it has become possible to determine the accumulation of tracer and correlate this to intraoperative fluorescence-based identification rates. In the current study, we determined the lower detection limit of tracer at which intraoperative fluorescence guidance was still feasible. METHODS: Size exclusion chromatography (SEC) provided a laboratory set-up to analyze the chemical content and to simulate the migratory behavior of ICG-nanocolloid in tissue. Tracer accumulation and intraoperative fluorescence detection findings were derived from a retrospective analysis of 20 head-and-neck melanoma patients, 40 penile and 20 prostate cancer patients scheduled for sentinel node (SN) biopsy using ICG-(99m)Tc-nanocolloid. In these patients, following tracer injection, single photon emission computed tomography fused with computed tomography (SPECT/CT) was used to identify the SN(s). The percentage injected dose (% ID), the amount of ICG (in nmol), and the concentration of ICG in the SNs (in µM) was assessed for SNs detected on SPECT/CT and correlated with the intraoperative fluorescence imaging findings. RESULTS: SEC determined that in the hybrid tracer formulation, 41 % (standard deviation: 12 %) of ICG was present in nanocolloid-bound form. In the SNs detected using fluorescence guidance a median of 0.88 % ID was present, compared to a median of 0.25 % ID in the non-fluorescent SNs (p-value < 0.001). The % ID values could be correlated to the amount ICG in a SN (range: 0.003-10.8 nmol) and the concentration of ICG in a SN (range: 0.006-64.6 µM). DISCUSSION: The ability to provide intraoperative fluorescence guidance is dependent on the amount and concentration of the fluorescent dye accumulated in the lesion(s) of interest. Our findings indicate that intraoperative fluorescence detection with ICG is possible above a µM concentration.

Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults.

AIMS: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is used in the treatment of mantle cell lymphoma or chronic lymphocytic leukaemia. Ibrutinib undergoes extensive rapid oxidative metabolism mediated by cytochrome P450 3A both at the level of first pass and clearance, which might result in low oral bioavailability. The present study was designed to investigate the absolute bioavailability (F) of ibrutinib in the fasting and fed state and assess the effect of grapefruit juice (GFJ) on the systemic exposure of ibrutinib in order to determine the fraction escaping the gut (Fg ) and the fraction escaping hepatic extraction (Fh ) in the fed state. METHODS: All participants received treatment A [560 mg oral ibrutinib, under fasting conditions], B (560 mg PO ibrutinib, fed, administered after drinking glucose drink) and C (140 mg oral ibrutinib, fed, with intake of GFJ before dosing). A single intravenous (i.v.) dose of 100 µg (13) C6 -ibrutinib was administered 2 h after each oral dose. RESULTS: The estimated 'F' for treatments A, B and C was 3.9%, 8.4% and 15.9%, respectively. Fg and Fh in the fed state were 47.0% and 15.9%, respectively. Adverse events were mild to moderate in severity (Grade 1-2) and resolved without sequelae by the end of the study. CONCLUSION: The absolute oral bioavailability of ibrutinib was low, ranging from 3.9% in the fasting state to 8.4% when administered 30 min before a standard breakfast without GFJ and 15.9% with GFJ. Ibrutinib was well tolerated following a single oral and i.v. dose, under both fasted and fed conditions and regardless of GFJ intake status.