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We are embarking on a first-in-human study for a novel pain drug. Our intention is to combine a first-time-in-human single ascending dose panel with a quick proof-of-concept to determine if the drug works. Any input into how this study can be designed so that patient safety is not compromised in any way yet we can get a quick peek in whether or not we should proceed with this? Any input would be appreciated. I would like to hear both pros and cons of going with this method? CRO representatives, please contact me ONLY IF you have experience carrying out these combo SAD-POC studies.
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The human safety would in part be dependant on the safety of the drug in the first place and then the design of the trial. According to the findings of your toxicology program, you may chose the safety factor for your starting dose. With preclinical PKPD data , you may be able to predict the human dose - concentration-response which further support your dose escalation design. Pharmacokinetic parameters from the SAD can be estimated (interim analysis) and refine the PKPD relationship and support the PoC / multiple dose design. Parameters like accumulation after multiple dosing can be predicted from the half life and frequenccy of administration which gives you an idea of your expected exposure in relation to your NOAEL level in the tox spieces.
In case you expect PD differences between the healthy volunteers and the patients population, this need to be considered when switching from the SAD to the PoC (in case you do your PoC in patients).
In case you are dealing with biologics (e.g. monoclonal antibodies, peptides, .....) and high risk compounds, particular attention should be made to the starting dose and the MABEL approach should be used.
Below is a couple of papers that can be of help.1- an example of a successful trial with AEB071 with SAD and PoC phase. 2- a review on selecting the human dose through PKPD.
1- The PKC inhibitor AEB071 may be a therapeutic option for psoriasis. J Clin Invest. 2008 Sep;118(9):3151-9. Skvara H, Dawid M, Kleyn E, Wolff B, Meingassner JG, Knight H, Dumortier T, Kopp T, Fallahi N, Stary G, Burkhart C, Grenet O, Wagner J, Hijazi Y, Morris RE, McGeown C, Rordorf C, Griffiths CE, Stingl G, Jung T.
2- On the anticipation of the human dose in first-in-man trials from preclinical and prior clinical information in early drug development. Xenobiotica. 2007 Oct-Nov;37(10-11):1331-54. Lowe PJ, Hijazi Y, Luttringer O, Yin H, Sarangapani R, Howard D. Kind Regards, Youssef
Youssef Hijazi, PharmD, PhD (pharmacokinetics)
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