The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Graham Lappin - One of the best experts on this subject based on the ideXlab platform.
-
Microdosing and other phase 0 clinical trials facilitating translation in drug development
Clinical and Translational Science, 2016Co-Authors: Tal Burt, Graham Lappin, Yuichi Sugiyama, Kenta Yoshida, L Vuong, Christy S John, S N De Wildt, Malcolm RowlandAbstract:A number of drivers and developments suggest that Microdosing and other phase 0 applications will experience increased utilization in the near-to-medium future. Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities are important drivers in favor of these approaches, and can be expected only to increase in their relevance. An increasing body of research supports the validity of extrapolation from the limited drug exposure of phase 0 approaches to the full, therapeutic exposure, with modeling and simulations capable of extrapolating even non-linear scenarios. An increasing number of applications and design options demonstrate the versatility and flexibility these approaches offer to drug developers including the study of PK, bioavailability, DDI, and mechanistic PD effects. PET Microdosing allows study of target localization, PK and receptor binding and occupancy, while Intra-Target Microdosing (ITM) allows study of local therapeutic-level acute PD coupled with systemic microdose-level exposure. Applications in vulnerable populations and extreme environments are attractive due to the unique risks of pharmacotherapy and increasing unmet healthcare needs. All phase 0 approaches depend on the validity of extrapolation from the limited-exposure scenario to the full exposure of therapeutic intent, but in the final analysis the potential for controlled human data to reduce uncertainty about drug properties is bound to be a valuable addition to the drug development process.
-
the expanding utility of Microdosing
Clinical pharmacology in drug development, 2015Co-Authors: Graham LappinAbstract:The concept of Microdosing has been around for more than a decade. It consists of the subpharmacologic administration of an investigational drug (1% of the pharmacologic dose or 100 µg, whichever is lower) to human subjects to attain pre-phase 1 pharmacokinetics (PK) in humans. The major concern with Microdosing has been the potential for nonlinear PK between doses, but methods are emerging to evaluate the potential for nonlinear PK prior to conducting a study. Currently, approximately 80% of drugs tested by the oral route and 100% by the intravenous route have exhibited scalable PK between a microdose and a therapeutic dose (within a factor of 2). Over the past few years Microdosing has found utility in pediatrics, protein-based therapeutics, and a new application known as intra-arterial Microdosing that focuses more on localized pharmacodynamics than PK. Compared with other PK predictive methods, such as physiologically based pharmacokinetic modeling, allometry, and in vitro-in vivo extrapolation, Microdosing appears to provide a significantly better understanding of PK prior to phase 1, albeit within what is currently a limited database.
-
Microdosing and drug development past present and future
Expert Opinion on Drug Metabolism & Toxicology, 2013Co-Authors: Graham Lappin, Robert J Noveck, Tal BurtAbstract:Introduction: Microdosing is an approach to early drug development where exploratory pharmacokinetic data are acquired in humans using inherently safe sub-pharmacologic doses of drug. The first publication of microdose data was 10 years ago and this review comprehensively explores the microdose concept from conception, over the past decade, up until the current date. Areas covered: The authors define and distinguish the concept of Microdosing from similar approaches. The authors review the ability of Microdosing to provide exploratory pharmacokinetics (concentration-time data) but exclude Microdosing using positron emission tomography. The article provides a comprehensive review of data within the peer-reviewed literature as well as the latest applications and a look into the future, towards where Microdosing may be headed. Expert opinion: Evidence so far suggests that Microdosing may be a better predictive tool of human pharmacokinetics than alternative methods and combination with physiologically based ...
-
predicting drug candidate victims of drug drug interactions using Microdosing
Clinical Pharmacokinectics, 2012Co-Authors: Marie Croft, Brendan J Keely, Ian D Morris, Lan Tann, Graham LappinAbstract:The aim of this crossover human male volunteer study was to investigate the utility of Microdosing in the investigation of drug-drug interactions. A mixture of midazolam, tolbutamide, caffeine and fexofenadine were administered as a micro-dose (25 mg each) before and after administration of a combined pharmacological dose of ketoconazole (400 mg) and fluvoxamine (100 mg) to inhibit P-glycoprotein and metabolism by cytochrome P450 (CYP) 1A2, CYP3A4 and CYP2C9. When administered alone, pharmacokinetics for all four microdosed compounds scaled well with those reported for therapeutic doses and with previously performed microdose studies. The pharmacokinetics of each compound administered as a microdose were significantly altered after the administration of ketoconazole and fluvoxamine, showing statistically significant (p < 0.01) 12.8-, 8.1- and 3.2-fold increases in the area under the plasma concentration-time curve from time zero to infinity (AUC∞) for midazolam, caffeine and fexofenadine, respectively. A 1.8-fold increase (not statistically significant) in AUC∞ was observed for tolbutamide. The changes in pharmacokinetics mediated by ketoconazole and fluvoxamine were quantitatively consistent with previously reported, non-microdose, drug-drug interaction data from studies including the same compounds. The initial data reported here demonstrate the utility of Microdosing to investigate the risk of development drugs being victims of drug-drug interactions.
-
Microdosing current and the future
Bioanalysis, 2010Co-Authors: Graham LappinAbstract:The concept of Microdosing has been around for approximately 10 years. In this time there have been an increasing number of drugs reported in the literature where the pharmacokinetics at a microdose have been compared with those observed at a therapeutic dose. Currently, approximately 80% of the microdose pharmacokinetics available in the public domain have been shown to scale to those observed at a therapeutic dose, within a twofold difference. Microdosing is now being extended into areas of drug development other than purely pharmacokinetic prediction. Microdosing has been applied to the study of drug-drug interactions by giving human volunteers a microdose of the candidate drug before and after the administration of a drug known to inhibit or induce certain enzymes, such as the cytochrome P450s. Early data on the metabolism of a drug candidate can be obtained by administering a (14)C-drug to human volunteers and comparing the plasma concentration-time curves for total (14)C and unchanged parent compound. Full metabolic profiles can be generated as an early indication of the drug's metabolism in humans, prior to Phase 1 clinical studies. Microdosing is also being applied to situations where the concentration of a drug in cell or tissue types is key to its efficacy. The application of Microdosing as a tool in drug development is therefore widening into new and previously unforeseen fields.
Oliver Langer - One of the best experts on this subject based on the ideXlab platform.
-
approaches using molecular imaging technology use of pet in clinical microdose studies
Advanced Drug Delivery Reviews, 2011Co-Authors: Claudia C Wagner, Oliver LangerAbstract:Positron emission tomography (PET) imaging uses minute amounts of radiolabeled drug tracers and thereby meets the criteria for clinical microdose studies. The advantage of PET, when compared to other analytical methods used in microdose studies, is that the pharmacokinetics (PK) of a drug can be determined in the tissue targeted for drug treatment. PET Microdosing already offers interesting applications in clinical oncology and in the development of central nervous system pharmaceuticals and is extending its range of application to many other fields of pharmaceutical medicine. Although requirements for preclinical safety testing for microdose studies have been cut down by regulatory authorities, radiopharmaceuticals increasingly need to be produced under good manufacturing practice (GMP) conditions, which increases the costs of PET Microdosing studies. Further challenges in PET Microdosing include combining PET with other ultrasensitive analytical methods, such as accelerator mass spectrometry (AMS), to gain plasma PK data of drugs, beyond the short PET examination periods. Finally, conducting clinical PET studies with radiolabeled drugs both at micro- and therapeutic doses is encouraged to answer the question of dose linearity in clinical Microdosing.
-
new ultrasensitive detection technologies and techniques for use in Microdosing studies
Bioanalysis, 2009Co-Authors: Graham Lappin, Claudia C Wagner, Oliver Langer, Nico C Van De MerbelAbstract:In a Microdosing study, subpharmacologically active doses of drug are given to human volunteers at an early stage of development in order to obtain preliminary pharmacokinetic data. The very low doses of drug administered (≤100 µg) consequently lead to very low concentrations of drug appearing in the body and therefore highly sensitive analytical techniques are required. There are three such analytical technologies currently used in Microdosing studies: PET, liquid chromatography (LC)-tandem mass spectrometry (MS/MS) and accelerator mass spectrometry (AMS). Both PET and AMS employ radioisotopic tracers. PET is an imaging technique and AMS is an extremely sensitive isotope ratio method, able to measure drug concentrations in the ag/ml range. LC-MS/MS does not require the presence of an isotopic tracer and its sensitivity is in the pg/ml range. This review examines each of these three analytical modalities in the context of performing Microdosing studies.
-
Microdosing studies in humans the role of positron emission tomography
Drugs in R & D, 2008Co-Authors: Martin Bauer, Claudia C Wagner, Oliver LangerAbstract:Positron emission tomography (PET)-Microdosing comprises the administration of a carbon-11- or fluorine-18-labelled drug candidate to human subjects in order to describe the drug’s concentration-time profile in body tissues targeted for treatment. As PET Microdosing involves the administration of only microgram amounts of unlabelled drug, the potential toxicological risk to human subjects is very limited. Consequently, regulatory authorities require reduced preclinical safety testing as compared with conventional phase 1 studies. Microdose studies are gaining increasing importance in clinical drug research as they have the potential to shorten time-lines and cut costs along the critical path of drug development. Current applications of PET in anticancer, anti-infective and CNS system drug research are reviewed.
-
positron emission tomography for use in Microdosing studies
Current Opinion in Drug Discovery & Development, 2008Co-Authors: Claudia C Wagner, Graham Lappin, Markus Muller, Oliver LangerAbstract:Positron emission tomography (PET) imaging using microdoses of radiolabeled drug tracers is gaining increasing acceptance in modern clinical drug development. This approach is unique in that it allows for direct quantitative assessment of drug concentrations in the tissues targeted for treatment, thereby bridging the gap between pharmacokinetics and pharmacodynamics. Current applications of PET in anticancer, anti-infective and central nervous system drug research are reviewed herein. Situated at the interface of preclinical and clinical drug testing, PET Microdosing is a powerful and highly innovative tool for pharmaceutical development.
-
a positron emission tomography Microdosing study with a potential antiamyloid drug in healthy volunteers and patients with alzheimer s disease
Clinical Pharmacology & Therapeutics, 2006Co-Authors: Martin Bauer, Oliver Langer, Peter Dalbianco, Rudolf Karch, Martin Brunner, Aiman Abrahim, Rupert Lanzenberger, Andrea Hofmann, Christian Joukhadar, Paolo CarminatiAbstract:This work describes a Microdosing study with an investigational, carbon 11-labeled antiamyloid drug, 1,1'-methylene-di-(2-naphthol) (ST1859), and positron emission tomography (PET) in healthy volunteers (n = 3) and patients with Alzheimer's disease (n = 6). The study aimed to assess the distribution and local tissue pharmacokinetics of the study drug in its target organ, the human brain. Before PET studies were performed in humans, the toxicologic characteristics of ST1859 were investigated by an extended single-dose toxicity study according to guidelines of the Food and Drug Administration and European Medicines Agency, which are relevant for clinical trials with a single microdose. After intravenous bolus injection of 341 +/- 21 MBq [(11)C]ST1859 (containing <11.4 nmol of unlabeled ST1859), peripheral metabolism was rapid, with less than 20% of total plasma radioactivity being in the form of unchanged parent drug at 10 minutes after administration. In both the control and patient groups, uptake of radioactivity into the brain was relatively fast (time to reach maximum concentration, 9-17 minutes) and pronounced (maximum concentration [standardized uptake value], 1.3-2.2). In both healthy volunteers and patients, there was a rather uniform distribution of radioactivity in the brain, including both amyloid-beta-rich and -poor regions, with slow washout of radioactivity (half-life, 82-185 minutes). In conclusion, these data provide important information on the blood-brain barrier penetration and metabolism of an investigational antiamyloid drug and suggest that the PET Microdosing approach is a useful method to describe the target-organ pharmacokinetics of radiolabeled drugs in humans.
Ronald Colin Garner - One of the best experts on this subject based on the ideXlab platform.
-
the application of accelerator mass spectrometry to absolute bioavailability studies in humans simultaneous administration of an intravenous microdose of 14c nelfinavir mesylate solution and oral nelfinavir to healthy volunteers
The Journal of Clinical Pharmacology, 2005Co-Authors: Nenad Sarapa, Poe-hirr Hsyu, Graham Lappin, Ronald Colin GarnerAbstract:The absolute bioavailability of nelfinavir was determined in 6 healthy volunteers following simultaneous administration of 1250 mg oral nelfinavir and an intravenous infusion of 14C-nelfinavir mesylate on day 1 and at steady state. Nelfinavir oral bioavailability decreased from 0.88 to 0.47 over the 11-day study period. The moderate bioavailability of nelfinavir was due to significant first-pass metabolism rather than low absorption, limiting the potential of formulation improvement to decrease pill burden. Human absolute bioavailability studies with accelerator mass spectrometry Microdosing, in which an intravenous microdose is given along with a conventional oral dose of the same drug, can differentiate between gastrointestinal absorption and the first-pass metabolism of new drug candidates. Accelerator mass spectrometry allowed a several thousand-fold dose reduction of 14C-nelfinavir relative to that required for liquid scintillation counting. Accelerator mass spectrometry Microdosing reduces potential safety issues around dosing radioactivity to humans and prevents the need to formulate high intravenous doses. ©2005 the American College of Clinical Pharmacology.
-
The application of accelerator mass spectrometry to absolute bioavailability studies in humans: simultaneous administration of an intravenous microdose of 14C-nelfinavir mesylate solution and oral nelfinavir to healthy volunteers.
Journal of clinical pharmacology, 2005Co-Authors: Nenad Sarapa, Poe-hirr Hsyu, Graham Lappin, Ronald Colin GarnerAbstract:The absolute bioavailability of nelfinavir was determined in 6 healthy volunteers following simultaneous administration of 1250 mg oral nelfinavir and an intravenous infusion of (14)C-nelfinavir mesylate on day 1 and at steady state. Nelfinavir oral bioavailability decreased from 0.88 to 0.47 over the 11-day study period. The moderate bioavailability of nelfinavir was due to significant first-pass metabolism rather than low absorption, limiting the potential of formulation improvement to decrease pill burden. Human absolute bioavailability studies with accelerator mass spectrometry Microdosing, in which an intravenous microdose is given along with a conventional oral dose of the same drug, can differentiate between gastrointestinal absorption and the first-pass metabolism of new drug candidates. Accelerator mass spectrometry allowed a several thousand-fold dose reduction of (14)C-nelfinavir relative to that required for liquid scintillation counting. Accelerator mass spectrometry Microdosing reduces potential safety issues around dosing radioactivity to humans and prevents the need to formulate high intravenous doses.
Tsontcho Ianchulev - One of the best experts on this subject based on the ideXlab platform.
-
latanoprost with high precision piezo print microdose delivery for iop lowering clinical results of the pg21 study of 0 4 µg daily microdose
Clinical Ophthalmology, 2018Co-Authors: Louis R Pasquale, Tsontcho Ianchulev, Robert N Weinreb, James C Tsai, Shan Lin, Robert L KrammAbstract:Author(s): Pasquale, Louis R; Lin, Shan; Weinreb, Robert N; Tsai, James C; Kramm, Robert L; Ianchulev, Tsontcho | Abstract: Background:Topical high-precision piezo-print delivery of microdoses of latanoprost achieved significant IOP reduction consistent with the eyedropper effect but with a 75% reduced exposure to drugs and preservatives. Prostaglandin analogs are a mainstay glaucoma therapy. However, conventional eyedroppers deliver 30-50 µL drops that greatly exceed the physiologic 7-µL ocular tear film capacity. Eyedropper overdosing floods the eye with excess drug compounds and preservatives, resulting in ocular surface toxicity, periorbitopathy, and other well-characterized ocular side effects. Piezoelectric high-precision Microdosing provides targeted delivery that can reduce exposure to both drug and preservatives compared to conventional eyedropper delivery, with the potential to deliver similar biologic effect. Methods:Both eyes (N=60) of 30 healthy volunteers received single 8-µL microdoses of 0.005% latanoprost (0.4 µg; µRx-latanoprost) on the morning of Days 1 and 2 using a high-precision, piezo-print horizontal delivery system. Diurnal IOP was measured before and 2 days after Microdosing. Main efficacy outcomes were diurnal IOP change after µRx-latanoprost Microdosing and accurate Microdosing success rates, and the primary safety outcome was adverse event (AE) incidence. Results:µRx-latanoprost reduced baseline IOP by 26% and 30% at 1 and 2 days postadministration, respectively. Successful topical dosing was achieved in 100% of technician-assisted deliveries. All patients successfully self-administered microdoses after receiving training. Microdose administration was well tolerated and did not result in any AEs. Conclusion:Microdosing of 0.4 µg of µRx-latanoprost achieved significant IOP reduction. Lower ocular exposure with topical prostaglandin analog Microdosing can enable new therapeutic opportunities for optimizing glaucoma treatment. Microdosing may also be beneficial in reducing ocular side effects associated with excessive drug product and preservatives often used to treat chronic ocular diseases such as glaucoma.
-
high precision piezo ejection ocular Microdosing phase ii study on local and systemic effects of topical phenylephrine
Therapeutic Delivery, 2018Co-Authors: Tsontcho Ianchulev, Robert N Weinreb, James C Tsai, Shan Lin, Louis R PasqualeAbstract:Aim: Conventional eyedropper-delivered volumes (25–50 µl) exceed the eye's usual tear-film volume (7 µl) and precorneal reservoir capacity, risking overflow and ocular/systemic complications. Piezoelectric high-precision Microdosing may circumvent these limitations. Results & methodology: In this masked, nonrandomized, cross-over study, subjects (n = 12) underwent pupil dilation with topical phenylephrine (PE) administered by 32-µl eyedropper (2.5% or 10% formulation) and 8-µl electronic Microdosing (10% formulation). Microdosing with PE-10% achieved comparable peak dilation as 10% eyedropper-delivery and superior dilation to 2.5% eyedropper-delivery (p = 0.009) at 75 min. Microdosing significantly reduced 20-min plasma PE levels versus PE10% eyedropper; neither treatment altered heart rate/blood pressure. Eye irritation occurred significantly less frequently with Microdosing than PE10% eyedrops. Conclusion: Piezo-ejection PE Microdosing achieves comparable biological effect as eyedropper dosing; reduced ...
-
Pharmacodynamic profile of mydriatic agents delivered by ocular piezo-ejection Microdosing compared with conventional eyedropper.
Therapeutic Delivery, 2016Co-Authors: Tsontcho Ianchulev, Louis R Pasquale, Arturo Chayet, Malik Y. Kahook, Mark Packer, Robert N WeinrebAbstract:Aim: Eyedroppers deliver medication volumes exceeding conjunctival absorptive capacity, causing spillage and risking ocular/systemic complications. We evaluated piezoelectric Microdosing. Results/methodology: Subjects (n = 102) received precision microdroplet delivery of phenylephrine (2.5%) and tropicamide (1.0%): 1 × 1.5 μl, 1 × 6 μl or 2 × 3 μl of each (randomized 1:1:1), into one eye. Contralateral eyes received eyedropper doses of both drugs. Outcomes were pupil dilation (0–60 min) and patient satisfaction. Six-microliter Microdosing achieved comparable, and 2 × 3 μl met/exceeded dilation speed and magnitude versus eyedropper. Separately, participants preferred piezoelectric saline self-delivery to eyedroppers, reporting better head-positioning comfort, reduced tearing/overflow and increased likelihood of adhering to ocular medication regimens. Conclusion: Piezoelectric Microdosing achieves comparable effects as eyedroppers delivering 4–17-fold larger doses. Microdosing may enhance patient adherence ...
Louis R Pasquale - One of the best experts on this subject based on the ideXlab platform.
-
latanoprost with high precision piezo print microdose delivery for iop lowering clinical results of the pg21 study of 0 4 µg daily microdose
Clinical Ophthalmology, 2018Co-Authors: Louis R Pasquale, Tsontcho Ianchulev, Robert N Weinreb, James C Tsai, Shan Lin, Robert L KrammAbstract:Author(s): Pasquale, Louis R; Lin, Shan; Weinreb, Robert N; Tsai, James C; Kramm, Robert L; Ianchulev, Tsontcho | Abstract: Background:Topical high-precision piezo-print delivery of microdoses of latanoprost achieved significant IOP reduction consistent with the eyedropper effect but with a 75% reduced exposure to drugs and preservatives. Prostaglandin analogs are a mainstay glaucoma therapy. However, conventional eyedroppers deliver 30-50 µL drops that greatly exceed the physiologic 7-µL ocular tear film capacity. Eyedropper overdosing floods the eye with excess drug compounds and preservatives, resulting in ocular surface toxicity, periorbitopathy, and other well-characterized ocular side effects. Piezoelectric high-precision Microdosing provides targeted delivery that can reduce exposure to both drug and preservatives compared to conventional eyedropper delivery, with the potential to deliver similar biologic effect. Methods:Both eyes (N=60) of 30 healthy volunteers received single 8-µL microdoses of 0.005% latanoprost (0.4 µg; µRx-latanoprost) on the morning of Days 1 and 2 using a high-precision, piezo-print horizontal delivery system. Diurnal IOP was measured before and 2 days after Microdosing. Main efficacy outcomes were diurnal IOP change after µRx-latanoprost Microdosing and accurate Microdosing success rates, and the primary safety outcome was adverse event (AE) incidence. Results:µRx-latanoprost reduced baseline IOP by 26% and 30% at 1 and 2 days postadministration, respectively. Successful topical dosing was achieved in 100% of technician-assisted deliveries. All patients successfully self-administered microdoses after receiving training. Microdose administration was well tolerated and did not result in any AEs. Conclusion:Microdosing of 0.4 µg of µRx-latanoprost achieved significant IOP reduction. Lower ocular exposure with topical prostaglandin analog Microdosing can enable new therapeutic opportunities for optimizing glaucoma treatment. Microdosing may also be beneficial in reducing ocular side effects associated with excessive drug product and preservatives often used to treat chronic ocular diseases such as glaucoma.
-
high precision piezo ejection ocular Microdosing phase ii study on local and systemic effects of topical phenylephrine
Therapeutic Delivery, 2018Co-Authors: Tsontcho Ianchulev, Robert N Weinreb, James C Tsai, Shan Lin, Louis R PasqualeAbstract:Aim: Conventional eyedropper-delivered volumes (25–50 µl) exceed the eye's usual tear-film volume (7 µl) and precorneal reservoir capacity, risking overflow and ocular/systemic complications. Piezoelectric high-precision Microdosing may circumvent these limitations. Results & methodology: In this masked, nonrandomized, cross-over study, subjects (n = 12) underwent pupil dilation with topical phenylephrine (PE) administered by 32-µl eyedropper (2.5% or 10% formulation) and 8-µl electronic Microdosing (10% formulation). Microdosing with PE-10% achieved comparable peak dilation as 10% eyedropper-delivery and superior dilation to 2.5% eyedropper-delivery (p = 0.009) at 75 min. Microdosing significantly reduced 20-min plasma PE levels versus PE10% eyedropper; neither treatment altered heart rate/blood pressure. Eye irritation occurred significantly less frequently with Microdosing than PE10% eyedrops. Conclusion: Piezo-ejection PE Microdosing achieves comparable biological effect as eyedropper dosing; reduced ...
-
Pharmacodynamic profile of mydriatic agents delivered by ocular piezo-ejection Microdosing compared with conventional eyedropper.
Therapeutic Delivery, 2016Co-Authors: Tsontcho Ianchulev, Louis R Pasquale, Arturo Chayet, Malik Y. Kahook, Mark Packer, Robert N WeinrebAbstract:Aim: Eyedroppers deliver medication volumes exceeding conjunctival absorptive capacity, causing spillage and risking ocular/systemic complications. We evaluated piezoelectric Microdosing. Results/methodology: Subjects (n = 102) received precision microdroplet delivery of phenylephrine (2.5%) and tropicamide (1.0%): 1 × 1.5 μl, 1 × 6 μl or 2 × 3 μl of each (randomized 1:1:1), into one eye. Contralateral eyes received eyedropper doses of both drugs. Outcomes were pupil dilation (0–60 min) and patient satisfaction. Six-microliter Microdosing achieved comparable, and 2 × 3 μl met/exceeded dilation speed and magnitude versus eyedropper. Separately, participants preferred piezoelectric saline self-delivery to eyedroppers, reporting better head-positioning comfort, reduced tearing/overflow and increased likelihood of adhering to ocular medication regimens. Conclusion: Piezoelectric Microdosing achieves comparable effects as eyedroppers delivering 4–17-fold larger doses. Microdosing may enhance patient adherence ...