Nature Reviews Drug Discovery
February 28, 2003
Graham Lappin, R. Colin Garner
257 citations
Early clinical drug development has seen little change in 20 years despite a 40% failure rate due to poor drug metabolism and pharmacokinetics. A new method called microdosing allows investigational drugs to be tested in humans earlier, enabling smarter candidate selection. Microdosing relies on two ultrasensitive techniques: positron emission tomography (PET) for pharmacodynamic information and accelerator mass spectrometry (AMS) for pharmacokinetic information. This approach permits safer human studies and reduces the use of animals in preclinical toxicology.
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.
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.
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.
Clinical Pharmacokinetics
February 16, 2012
Marie Croft, Brendan J. Keely, Ian D. Morris et al.
42 citations
A crossover study in healthy male volunteers tested whether microdosing (25 μg each of midazolam, tolbutamide, caffeine, and fexofenadine) can detect drug-drug interactions. After administering pharmacological doses of ketoconazole (400 mg) and fluvoxamine (100 mg) to inhibit key metabolic enzymes and transporters, the microdosed compounds showed significant pharmacokinetic changes: area under the curve increased 12.8-fold for midazolam, 8.1-fold for caffeine, and 3.2-fold for fexofenadine (all p < 0.01), and 1.8-fold (not significant) for tolbutamide. These changes matched those reported in conventional drug-drug interaction studies, demonstrating microdosing's utility for assessing whether development drugs are victims of interactions.
Bioanalysis
March 1, 2010
Graham Lappin
36 citations
Microdosing, a technique used for about ten years, allows researchers to compare the pharmacokinetics of a very low drug dose with those at a therapeutic dose. About 80% of available microdose pharmacokinetic data scale within a twofold difference of therapeutic doses. The method is expanding beyond pharmacokinetic prediction into areas like studying drug-drug interactions, where volunteers receive a microdose before and after an enzyme-inhibiting or -inducing drug. It also helps obtain early metabolic profiles by administering a 14C-labeled drug and comparing total and unchanged compound concentrations. Microdosing is now being applied to assess drug concentrations in key cell or tissue types, broadening its use in drug development.
Clinical Pharmacology in Drug Development
November 1, 2015
Graham Lappin
Microdosing involves giving human subjects a subpharmacologic dose (1% of the pharmacologic dose or 100 µg, whichever is lower) of an investigational drug to obtain pre–phase 1 pharmacokinetic data. A key concern is nonlinear pharmacokinetics between microdoses and therapeutic doses, but methods to evaluate this nonlinearity are emerging. Currently, about 80% of drugs tested orally and 100% intravenously show scalable pharmacokinetics within a factor of 2. Microdosing has recently been applied in pediatrics, protein-based therapeutics, and intra-arterial microdosing for localized pharmacodynamics. Compared with other predictive methods, microdosing appears to provide a significantly better understanding of pharmacokinetics before phase 1, though the database remains limited.