What is the test-item with which you have performed the acute study? May I ask you the reason for performing acute toxicity study..what were you trying to find out? Also, if possible, kindly inform the findings from your acute study?

I can give a proper reply after knowing this..

Attaching a relevant guideline.

Varun Ahuja Sir, I am working on the screening of antimalarial compounds. I found one compound to be very promising. So, I have checked toxicity of the compound against various cell lines at different concentrations. I have also checked the acute toxicity of the compounds at 2000 and 300 mg/kg body weight of mice according to OECD Guidelines. My next plan is to do antimalarial studies in mice. I would like to know about the importance of sub-acute toxicity in my study.

Hi Priyanka, so you have checked the efficacy, in vitro toxicity and acute toxicity of your lead compound, so far. Let's hope that you find a very good compound and would like to submit it to US-FDA for approval.

Therefore, the procedure is to perform exploratory toxicity studies to ascertain that your compound is safe enough, and when you are confident about your lead compound than you need to do regulatory GLP studies for IND submission.

Let's start point-wise:

1. Acute in vivo studies are not needed for pharmaceuticals (Ref. Chapman & Robinson 2007, Barle et al 2012 - attached).

2. A MTD/Repeat dose range finding study is needed. I have attached a table from a book chapter (Chapter 2: General Toxicology. In: Handbook of Toxicology, 3rd Edn.). This book is good, and I recommed it for you to understand the pharmaceutical toxicity testing, as I can't describe everything here.

3. ICHM3-R2 guideline describes the studies needed for pharmaceuticals for initiating human clinical trials and marketing. See Table 1 in this guideline, which describes the duration of repeat dose preclinical toxicity studies needed for initiating clinical trials of a drug with defined clinical duration. ICH guidelines are applicable for drug testing and an introductory reference listing various guidelines is attached (Ref. Wang et al 2010).

4. The information you derive from a MTD/Repeat (may be 1-3 week duration) is then used to determine dosage for a 28-day study, which could be further used to determine dosages for a 3 month study, and similarly for a 6-month study, as per requirement.

5. I hope you understand that information from a single dose acute study will not give you the idea about dosage for a 3 month study. It is possible that your dosages might be so high that it could kill all animals due to toxicity, or so low that no toxic symptoms are seen. Dose selection in animal studies should be so that the low dose should provide no adverse effects, the middle dose should have some effects, and high dose should give sufficient toxicity effects; the aim is to derive a NOAEL. (Ref. Dorato & Engelhardt 2005, Buckley & Dorato 2009, LASA 2009-attached)

6. This NOAEL and related toxicity information is then provided to clinical team (medical doctors), who use it to initiate human trials by deciding human dose from this data. See Appendix of attached FDA guidance "Estimating the maximum safe starting dose....". Also see attachment in attached FDA guidance "Guidance for Industry, Investigators.....".

I hope now you know why to perform sub-acute toxicity study for your compound.

Varun Ahuja Sir The test item is a potent drug extracted from bacteria against Plasmodium falciparum. This drug showed promising antiplasmodial activity in vitro and in cell lines. So, I want to extrapolate my work by testing its efficacy in vivo but prior to that, I performed the acute toxicity study according to OECD.