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Advanced Drug Delivery Reviews (v.63, #7)
New strategy for drug development with exploratory IND studies: Scientific basis and future directions
by Shinji Yamashita (Theme Editor); Yuichi Sugiyama (Theme Editor) (pp. 493-493).
Impact of microdosing clinical study — Why necessary and how useful? by Yuichi Sugiyama; Shinji Yamashita (pp. 494-502).
The microdose (MD) clinical study enables to select a “better” compound for new drug candidate that shows desirable PK profiles in human. This new methodology is highly expected to streamline the drug development and to increase the success probability in the clinical trial. Since only a small amount of the test compound (less than 100μg) is administered, the risk of harmful events to a human subject is regarded as minimal in the MD clinical study. However, the low dose also incurs the arguments about the usefulness of this method, since it may result in different PK profiles of drugs from that at the therapeutic dose. In addition, information on the efficacy/safety of the test compound cannot be obtained from the MD clinical study. On the other hand, PBPK model analysis based on the data of both the MD clinical study and in vitro study on metabolism, transport and binding enables the accurate prediction of PK profiles in humans at the therapeutic dose. PET molecular imaging technology further enhances the usability and applicability of the MD clinical study by offering the information on efficacy/safety. These methodologies, if coordinated effectively, are expected to innovate the new drug discovery and development.
Keywords: Microdose clinical study; Exploratory IND study; Drug development; Model and simulation; Molecular imaging
Ethical, legal, and social implications (ELSI) of microdose clinical trials by Chieko Kurihara (pp. 503-510).
A “microdose clinical trial” (microdosing) is one kind of early phase exploratory clinical trial, administering the compound at doses estimated to have no pharmacological or toxicological effects, aimed at screening candidates for further clinical development. This article's objective is to clarify the ethical, legal, and social implications (ELSI) of such an exploratory minimum-risk human trial. The definition and non-clinical study requirements for microdosing have been harmonized among the European Union (EU), United States (US), and Japan. Being conducted according to these regulations, microdosing seems to be ethically well justified in terms of respect for persons, beneficence, justice, human dignity, and animal welfare. Three big projects have been demonstrating the predictability of therapeutic dose pharmacokinetics from microdosing. The article offers suggestions as how microdosing can become a more useful and socially accepted strategy.
Keywords: Microdose; Ethics; Human dignity; Human screening; Belmont report; Drug development strategy
Comparative requirements for exploratory clinical trials — eIND, eCTA and microdosing by Patrick Y. Muller (pp. 511-517).
Exploratory clinical trials provide a strategy for rapid human entry of investigational drugs. Such clinical studies are typically conducted during early clinical development in phase I as first-in-human studies, have no therapeutic intent, are not intended to examine clinical tolerability and involve a small number of human subjects at limited dose/exposure. Early decision data derived from such clinical studies may include PK, PD and/or biomarker-based translational medicine endpoints as well as PK/PD modeling approaches. This review critically discusses the various exploratory clinical trial strategies, their advantages and disadvantages as well as the regulatory safety requirements. In this respect, strategies for exploratory Investigational New Drugs (eIND), exploratory Clinical Trial Applications (eCTA) and microdosing are highlighted and compared in view of the new ICH M3(R2) guideline including options for biotechnology-derived pharmaceuticals such as monoclonal antibodies.
Keywords: Safety assessment; Exploratory; Clinical trial; Microdosing; eIND; eCTA; Toxicology; Toxicity study; First-in-human; Translational medicine
Quantifying exploratory low dose compounds in humans with AMS by Stephen R. Dueker; Le T. Vuong; Peter N. Lohstroh; Jason A. Giacomo; John S. Vogel (pp. 518-531).
Accelerator Mass Spectrometry is an established technology whose essentiality extends beyond simply a better detector for radiolabeled molecules. Attomole sensitivity reduces radioisotope exposures in clinical subjects to the point that no population need be excluded from clinical study. Insights in human physiochemistry are enabled by the quantitative recovery of simplified AMS processes that provide biological concentrations of all labeled metabolites and total compound related material at non-saturating levels. In this paper, we review some of the exploratory applications of AMS14C in toxicological, nutritional, and pharmacological research. This body of research addresses the human physiochemistry of important compounds in their own right, but also serves as examples of the analytical methods and clinical practices that are available for studying low dose physiochemistry of candidate therapeutic compounds, helping to broaden the knowledge base of AMS application in pharmaceutical research.
Keywords: Microdosing; Accelerator Mass Spectrometry (AMS); Metabolism; Microdose; Mass balance; Nutrition; Physiochemistry; MIST; Microtracing; Absolute bioavailability; Microtracer
Novel strategies for microdose studies using non-radiolabeled compounds by Kazuya Maeda; Yuichi Sugiyama (pp. 532-538).
Microdose studies using non-radiolabeled compounds enable assessment of the clinical pharmacokinetics of drug candidates in humans without the need to synthesize radiolabeled compounds. We have demonstrated that the quantification limits of many drugs measured by LC–MS/MS are low enough to allow estimation of their pharmacokinetic parameters following administration of a microdose. Our previous microdose studies with LC–MS/MS demonstrated the linear pharmacokinetics of fexofenadine between microdoses and therapeutic doses. We also obtained time profiles of plasma concentrations of nicardipine and its multiple metabolites following administration of a microdose. A significant advantage of using non-radiolabeled compounds is the ability to perform cassette microdose studies. By administering multiple drug candidates to the same subject, we can select compounds with appropriate pharmacokinetic properties simultaneously. We can also clarify major factors dominating the pharmacokinetics of drug candidates by cocktail microdosing of the test compounds and probe substrates with or without specific inhibitors for enzymes/transporters.Display Omitted
Keywords: Abbreviations; ADME; absorption, distribution, metabolism and excretion; AMS; accelerator mass spectrometry; AUC; area under the plasma concentration–time curve; BSEP; bile salt export pump; C; max; maximum plasma concentration; CYP; cytochrome P450; DIN; drug interaction number; EUMAPP; European Microdosing AMS Partnership Program; K; i; inhibition constant; K; m; Michaelis constant; LC–MS/MS; liquid chromatography–tandem mass spectrometry; LIT–FTICRMS; linear ion trap–Fourier transform ion cyclotron resonance mass spectrometry; MRP2; multidrug resistance-associated protein 2; OAT3; organic anion transporter 3; OATP; organic anion transporting polypeptide; P-gp; P-glycoprotein; V; max; maximum velocity of reactionLC–MS/MS; Probe drugs; Genetic polymorphism; Drug–drug interaction; Cassette dosing; Transporter
Approaches using molecular imaging technology — use of PET in clinical microdose studies by Claudia C. Wagner; Oliver Langer (pp. 539-546).
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.Display Omitted
Keywords: Positron emission tomography (PET); Pharmacokinetics; Microdosing; Radioisotope; Small-animal PET; Good manufacturing practice (GMP); Dose linearity
Molecular imaging with SPECT as a tool for drug development by Célia M. Gomes; Antero J. Abrunhosa; Pedro Ramos; Ernest K.J. Pauwels (pp. 547-554).
Molecular imaging techniques are increasingly being used as valuable tools in the drug development process. Radionuclide-based imaging modalities such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have proven to be useful in phases ranging from preclinical development to the initial stages of clinical testing. The high sensitivity of these imaging modalities makes them particularly suited for exploratory investigational new drug (IND) studies as they have the potential to characterize in vivo pharmacokinetics and biodistribution of the compounds using only a fraction of the intended therapeutic dose (microdosing). This information obtained at an early stage of clinical testing results in a better selection among promising drug candidates, thereby increasing the success rate of agents entering clinical trials and the overall efficiency of the process. In this article, we will review the potential applications of SPECT imaging in the drug development process with an emphasis on its applications in exploratory IND studies.
Keywords: SPECT; Drug development; Microdosing; Pharmacokinetics; Imaging biomarkers