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Graham Lappin

Roche (Switzerland)

5 papers in the library · 727 citations · publishing 2003-2013

Papers

Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs

Clinical Pharmacology & Therapeutics September 1, 2006 Graham Lappin, W. Kuhnz, R. Jochemsen et al. 242 citations

A volunteer trial compared how five drugs—warfarin, ZK253, diazepam, midazolam, and erythromycin—are handled by the body when given as a microdose (100 micrograms) versus a standard therapeutic dose. For diazepam, midazolam, and ZK253, the microdose closely matched the therapeutic dose in key measures such as half-life, clearance, volume of distribution, and oral bioavailability. Warfarin's clearance was reasonably predicted from the microdose, but its volume of distribution differed, likely due to high-affinity, low-capacity tissue binding. The oral microdose of erythromycin produced no detectable blood levels, possibly because stomach acid destroyed it. Overall, microdosing can help select promising drug candidates early, if used appropriately.

DOI: 10.1016/j.clpt.2006.05.008 Microdose Pharmacokinetics Pharmacology Therapeutic index +8

Microdosing and drug development: past, present and future

Expert Opinion on Drug Metabolism & Toxicology April 4, 2013 Graham Lappin, Robert J. Noveck, Tal Burt 97 citations

Microdosing uses inherently safe, sub-pharmacologic doses of drug to acquire exploratory pharmacokinetic data in humans early in drug development. A decade after the first microdose data publication, evidence suggests microdosing may predict human pharmacokinetics better than alternative methods. Combining microdosing with physiologically based modeling could yield more reliable future predictions. The concept has been applied to drug-drug interactions, polymorphism, and assessing drug concentrations over time at the site of action. Microdosing may offer additional unanticipated benefits not yet fully realized.

DOI: 10.1517/17425255.2013.786042 Full text Microdose Drug development Medicine Pharmacology +2

The utility of microdosing over the past 5 years

Expert Opinion on Drug Metabolism & Toxicology November 28, 2008 Graham Lappin, R Colin Garner 89 citations

A review of 18 drugs found that 15 showed linear pharmacokinetics, meaning their drug concentration profiles at a microdose (≤100 micrograms) fell within a factor of two of those at a therapeutic dose. This supports the use of microdosing in Phase 0 trials to predict how a drug will behave at clinically relevant doses, helping to select candidates for further testing.

DOI: 10.1517/17425250802531767 Microdose Pharmacokinetics Pharmacology Clinical trial +3