Dr.Pravin ☆ Ahmedabad, 2006-10-30 07:23 (6385 d 15:19 ago) Posting: # 332 Views: 7,370 |
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Good Morning Dear, I want to know about the specific guidline which give me the details about the steady state study for long half life drugs (with active metabolites). I face problem with design issue and protocol preparation. reply me soon Regards Dr Pravin Ahir — Dr.Pravin Ahir Co-Investigator, Accutest Research Pvt.Lab.(I), Ltd. Ahmedabad |
Helmut ★★★ Vienna, Austria, 2006-10-30 15:22 (6385 d 07:20 ago) @ Dr.Pravin Posting: # 342 Views: 9,666 |
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Dear Pravin! ❝ I want to know about the specific guidline which give me the details about the steady state study for long half life drugs(with active metabolites). I don't know of any specific guidelines, but may give you some hints: In order to reach steady state conditions, you should apply the accumulation index for the compound (often a metabolite) with the longest half life first (although strictly speaking only valid for a one-compartment model, it may serve as a first approximation): 1 whereas R Accumulation index (concentrations in steady state compared to single dose) kel Elimination rate constant τ Dosage intervalFor example if your drug has an elimination half life of 16 hours and you are dosing once a day, R = 1.55; if your drug's half life is 30 hours, R = 2.45. First you should play around with this formula, in order to figure out whether
You should also consider any known genetic polymorphism of the drug; in such a case you should only include panels of subjects of known phenotype or genotype for the polymorphism in question (i.e., 'fast' or 'extensive' metabolizers). As a general rule you may expect steady state conditions after at least 3 half lives, but I would recommend at least 5 half lives. Unfortunatelly your problem is a quite nasty one, so this post may only serve as an entry point... At least you don't have to bother about a wash-out period, because you directly switch from one formulation to the other. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
Dr.Pravin ☆ Ahmedabad, 2006-10-31 06:15 (6384 d 16:26 ago) @ Helmut Posting: # 345 Views: 5,922 |
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Ya You are true but, drug like Fluoxetine and its active metabolite Norfluoxetine half life is 90 hrs so in such cases what we do. — Dr.Pravin Ahir Co-Investigator, Accutest Research Pvt.Lab.(I), Ltd. Ahmedabad |
Helmut ★★★ Vienna, Austria, 2006-10-31 13:28 (6384 d 09:14 ago) @ Dr.Pravin Posting: # 348 Views: 6,344 |
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Dear Pravin! ❝ [...] drug like Fluoxetine and its active metabolite Norfluoxetine half life is 90 hrs so in such cases what we do. OK, this is really a quite nasty compund. Just as an example have a look at this paper: Pan RN, Chen TH, Huang CSH, and CH Hsiong Since for normal distributed data P(mu+sigma) = 0.15866, one may assume that at least one subject (0.15866×8) showed a half life of >87.2+37.2 or more than 124.4 hours, therefore steady state conditions were not obtained in all subjects… BTW, Martindale (2002) reports a half life of 4-16 days for norfluoexetine, which also makes steady-state conditions in healthy subjects infeasible. At least you may opt for a parallel design, OAD dosing. Quoting A Marzo In such a case IMHO it is imperative to go for a ‘Scientific Advisory Meeting’ with the regulators in the planning phase of the study. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |