Clinical Pharmacokinetic Studies in Drug Development

I wanted to compile a list of various PK studies conducted during the course of drug development. Several studies are conducted in the early phase of clinical development to understand the pharmacokinetics (PK) of a new drug in healthy human volunteers and/or patients. The objective of such PK studies is to evaluate the absorption, distribution, metabolism and excretion (ADME) of a new drug in humans.

Information gathered during these studies include PK parameters such as area under the curve (AUC, exposure), Cmax (maximum concentration) , Tmax (Time to Cmax), half life, clearance, volume of distribution, bioavailability, steady state plasma concentrations, accumulation ratio, linear or nonlinear PK, time dependent PK (auto-induction), plasma protein binding, metabolite identity and their PK.

Here goes the list.

1. Single Ascending Dose (SAD)
2. Multiple Ascending Dose (MAD)
3. Food Effect Studies
4. ADME Mass Balance Studies
5. Absolute/Relative Bioavailability
6. Thorough QTc Study
7. Drug Interaction Studies - Enzyme Inhibition/Induction
8. Effect of Age and Gender
9. Special Population - Hepatic Impairment
10. Special Populaiton - Renal Impairment
11. Impact of Genetic Polymorphisms of Drug Metabolizing Enzymes

I will be blogging on each of these topics in the next few weeks. I am quite keen to know how modeling & simulation approaches have been used in early clinical PK studies. Feel free to share your thoughts/comments, any unusual experiences in the conduct of these studies.

Phase 0 Microdosing/Microtracing in Phase 1 Studies

Stephen Dueker, PhD, President/CEO of Vitalea Science recently commented on my previous post on Microdosing Studies. I thought of posting his comments and his email content pertaining to Microdosing/Microtracer studies in Phase 1 as a fresh post. Steve has also generously provided his recent presentation at ASMS meeting to be posted on this blog.

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All the methods and procedures for bioAMS were developed at Lawrence Livermore National Lab (LLNL) and the latest technology, the BioMICADAS developed by ETH/Zwitzerland and Vitalea Science (who has the original developer of bioAMS). It is important that people know the history of bioAMS and that it was the results of 15 years of intense research at Livermore in genotoxicity, nutrition, chemical interactions, pharmacology, and enviornmental studies. Other companies simply transferred some of the methods from LLNL.


What needs to be understood is that AMS is much more than Phase 0. As a CRO, many companies are doing microdosing as a means of "understanding the physiochemistry" of their compounds. The predictive PK topic is not the primary objective of microdosing, as PK can be solved later in formulation development. Microdosing is early ADME and understanding of the human metabolism. Receptor binding, tissue biopsies, cell loading, routes of elimination, protein binding, biotransformation, etc...can all be ascertained in a microdosing study. This indeed is what the specificity of a tracer and the sensitivity of AMS uncover.


There is a growing body of evidence that microdosing is predictive of macrodose PK, but again, that is not our (Vitalea's) principal focus nor would it be if I were a drug developer. Rank ordering multiple candidates is an interesting idea to supplant animal testing and I am surprised it is not used more, but generally developers are pretty attached to "their" candidate - thus we see scientists simply want to learn more so that they can have more efficient later Phase trials with fewer surprises. Analyses that we have been asked to do in microdosing proper are

• Prodrug metabolism
• Cellular penetration (Cell Loading)
• Confirm absence or presence of unwanted metabolites
• Potential for protein binding
• Balance (does the drug come out).

I think this last point is important, as one will never see deep reservoirs with macrodose ADME clearly. We have seen drug material leak out for weeks in some cases for a 6 hr half-life drug. None of it is parent drug. When these drugs become daily doses, these reservoirs accumulate and essentially lead to self-drugging by the drug and its metabolites. The impact this could have on idiosyncratic adverse events and safety in general, is real, and should be known in advance. Macrodoses swamp the system and tell little of the PhysioKemistry that is alway active, but not perceptible.


It is everyone’s desire to find a panacea to the complexity of drug development. Perhaps that is unrealistic. I see a new age where companies spend more time on their molecules, understanding and viewing metabolism and PhysioKemistry not as a nuisance, but as a tool to understand the drug fully (or class of compounds) avoid the potential for later stage surprises, and streamline IND phase testing once it commences.


The marginal relevance of animal testing is clear despite the objections of the preclin crowd (no disrespect here) - how can sub-therapeutical human data not be valuable in myriad ways. That is the question to be asked? Not is microdosing predictive of macrodose PK. Pharmacokinetic prediction is great, but metabolism impacts safety in unexpected ways. Microdosing or Phase 1 ADME using microtracers is a very good option to make better decisions.The hot topic is now MIST guidance, not so much Phase 0. AMS finds all metabolites without method development or internal standards.


Just coming back from ASMS, it is clear that MIST guidance has put a good deal of "concern" into the pharma business about how to address this important safety issue of steady state metabolite exposure. While my head is still trying to sort through the myriad configurations of hybridized MS instrumentation, the common theme running through all the very excellent MS talks was that radioanalysis is the most straightforward and absolute means of addressing MIST. Non-traditional radioanalysis, using AMS, expedites the entire endeavor.

It would appear that the field has come full circle - nothing is so powerful as a near 0 background analysis (14C) for unequivocal metabolite discovery, After discovery, one would then need to enlist the many sophisticated and quite impressive MS techniques for metaID when odd metabolites are revealed.

I do not see PK as the most important issue. Safety and Efficacy are the issue, and PhysioKemistry provides a view into processes that impact the later. This is a complex business. I am not sure if "more shots on goal" by emphasizing speed over understanding is the way to go.

Steve

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Feel free to discuss and share your experience with Microdosing/AMS/Microtracer studies.