Author information Article notes Copyright and License information Disclaimer. Sarina Tanimoto, Email: moc. Corresponding author. Received Aug 29; Accepted Nov This article has been cited by other articles in PMC. Subjects Eligible subjects were healthy male and female adult volunteers 18 to 55 years old, inclusive, with a body weight 51 kg to kg, inclusive. Statistical and Pharmacokinetic Analyses A target of 36 enrollees was planned with the goal of 24 completers.
Results Population A total of 36 subjects were enrolled and received at least 1 dose of drug. Open in a separate window. Ranges in subscripts indicate time intervals of measurements. Figure 1. Figure 2. Figure 3. Safety and Tolerability Nearly all the subjects Conflicts of Interest S. Funding This study was supported by Neurelis, Inc. Acknowledgments Medical writing support was provided at the direction of the authors by E. References 1. Epilepsy Collaborators. Lancet Neurol.
Centers for Disease Control and Prevention. Epilepsy Data and Statistics. Accessed April 22, The consequences of refractory epilepsy and its treatment. Epilepsy Behav. Seizure cluster: definition, prevalence, consequences, and management.
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I salute the experimental effort involved. Derek has indicated that calculated logD is probably accepted as accurate more often than it should be. The data in both these papers is impressive. The log-log plots definitively show trends, but they also sort of obscure the very large amount of scatter that is left unexplained by the correlations discussed in the paper. I think deep learning approaches, much ballyhooed by the commentariat here, would be very useful to apply to these data.
Even modest improvements in the accuracy of PK predictions would be a big advance! The volume of distribution of the drug was huge. The animals in long-term dosing study developed adrenal necrosis. Now the chances are that the drug candidate with such a troubled PK profile would not have been advanced at a risk-averse pharma company, and even as Pfizer people hated the project when they acquired Pharmacia-SUGEN, and proceeded rapidly to dismantle the team behind it, the things were quite far along with Sutent in the clinic and they did not cancel it.
Now it makes billions for Pfizer. As it happens, I worked on a follow-on analogs of Sutent with improved PK profile. We solved the problems with active metabolites and the organ accumulation, and our compound got into phase 1 and 2, after which it was shelved.
It turns out that toxicities of Sutent were manageable, and the improved analog did not offer anything new in terms of efficacy. And it had to be dosed higher, bi-daily, because it did not accumulate and had reduced lipophilicity and smaller volume of distribution. In fact, it now seems that the organ accumulation of Sutent is important for the therapeutic effect of Sutent.
So be careful what you are trying to fix. Eventually, someone persevered, learned to monitor levels in leukocytes instead of plasma. The plasma compartment is only rarely the target compartment. The unbound concentration in the plasma compartment is still important since, in the absence of active transport, it drives unbound concentrations in other compartments.
Is azithromycin actively transported into leukocytes? Hi All, thanks for the comments and the interest, I will try to address what I can in the next few lines. Some might be familiar with experiments with albumin deficient AD mice showing that the same compound in WT vs AD show comparable unbound concentration, but different total concentration.
After an IV dose, we can derived V from the concentration at time 0 and the Amount. Important to keep in mind Vtissue is the refers to the volume of water in tissues. If we now take 2 compounds with same tissue binding, the compound with higher Vdu is the compound with higher ability to distribute in tissue water. All rights Reserved. Former Hogwarts School of Thermodynamics says:. Nate says:. Peter Kenny says:. Sulphonamide says:.
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