Microdose

Sarapa, N., Early human microdosing to reduce attrition in clinical drug development, Am. Pharm. Outsourcing, 4, 42-46, 2003. 

Clinical trials are divided into four phases. These are Phase I to Phase IV (Fig. 6.1). These trials are conducted with specihc purposes to evaluate the safety and effectiveness of the drug in defined population groups. A recent proposal is to conduct Phase 0 —a microdosing trial on subjects. Exhibit 6.4 provides more details on this new topic. 

Lappin G, Garner RC. Big physics, small doses the use of AMS and PET in human microdosing of development drugs. Nat Rev Drug Discov 2003 2 233 0. 

Crooks, M.J. and Schade, H.W., Fluidized bed granulation of a microdose pharmaceutical powder. Powder Tech., 19 (1978) 103-108. 

M. Bergstrom, A. Grahnen, B. Langstrom, Positron emission tomography microdosing A new concept with application in tracer and early clinical drug development, Eur. J. Clin. Pharmacol. 59 (2003) 357-366. 

In a recent example, a sensitive LC-MS/MS method was successfully applied to assay for fexofenadine in plasma following a single oral administration of a microdose (100-pg solution) and a clinical dose (60-mg dose) to eight healthy volunteers (Yamane et al., 2007). Fexofenadine and terfenadine (IS) eluted at 0.95 and 2.07 min, respectively, and the correct m/z for the protonated precursor ions were observed at m/z 502.2 and 472.2. For SRM (or MRM) experiments, both precursor ions were fragmented separately in the collision cell and the fragment ions of m/z 466 and 436, respectively, were monitored for fexofenadine and terfenadine. The details of the fexofenadine assay are given in the following ... 

Using the sensitive quantitative LC-MS/MS method described above, linear PK profiles between clinical dosing and microdosing were obtained. Furthermore, Yamane et al. (2007) demonstrated that concentrations in human plasma after an oral dose of 100 pig is quantifiable using LC-ESI-MS/MS (Fig. 1.6), similar to what can be achieved using AMS (Chapter 2). 

Figure 1.6. Fexofenadine calibration curves and mean plasma concentration-time profiles following a single oral administration of (a) 100 pug (microdosing) or (b) 60 mg (clinical dosing) fexofenadine to healthy volunteers. (Reprinted with pemnission from Yamane et al., 2007.)...

Lebre, D. T., Aiello, M., Impey, G., and Bonelli, F. (2007). Microdosing study in rat plasma using high sensitive LC-ESI/MS/MS technique. In Proceedings of the 55th ASMS Conference on Mass Spectrometry and Allied Topics. ASMS, Indianapolis, IN. 

Yamane, N., Tozuka, Z., Sugiyama, Y., Tanimoto, T., Yamazaki, A., and Kumagai, Y. (2007). Microdose clinical trial Quantitative determination of fexofenadine in human plasma using liquid. J. Chromatogr. B 858 118-128. 

Supporting Microdosing Strategy with Triple-Quadrupole... 

Figure 2.10. The microdosing strategy for candidate selection offers the greatest benefit when a stop-development decision is made. This is because the exploratory IND does not forego the submission of a traditional IND to continue testing in the clinic. (IND, Investigational new drug mths, months FIH, First-in-human clinical study Ph1, Phase 1 clinical studies Ph2, Phase 2 clinical studies.)...

Although the lower limit of quantitation is established during assay validation and prior to microdosing, assay sensitivity remains an uncertainty until the actual analysis of the microdose samples as well. There is always the danger that plasma exposures from the microdose are lower than predicted and as a result plasma concentrations from some or all of the time points cannot be detected by the LC-MS/MS method. Reduction of this risk is achieved by collaborative communication between the bioanalytical chemist and the project team. Conservative estimates on bioavailability and clearance can be used to establish the necessary limit of detection needed to determine plasma concentrations for all time points. Updates on the progress of the assay development allow the team to decide if the achievable limit of detection will enable the determination of plasma concentrations from enough time points to make a go-no go decision. Of course, sensitivity is not an issue with AMS, which practically ensures that plasma concentrations will be determined, possibly for several days, enabling the observation of complex PK and clearance from deep compartments. 

Bertino, J. S., Jr., Greenberg, H. E., and Reed, M. D. (2007). American College of Clinical Pharmacology position statement on the use of microdosing in the drug development process. J. Clin. Pharmacol. 47 418-422. 

European Medicines Evaluation Agency (EMEA) (2003). Position paper on non-clinical safety studies to support clinical trials with a single microdose. EMEA, London, UK. 

Lappin, G., Kuhnz, W., Jochemsen, R., Kneer, J., Chaudhary, A., Oosterhuis, B., Drijfhout, W. J., Rowland, M., and Gamer, R. C. (2006a). Use of microdosing to predict pharmacokinetics at the therapeutic dose Experience with 5 drugs. Clin. Pharmacol. Ther. 80 203-215. 

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