Sridhar.E ☆ India, 20201008 10:23 (50 d 10:22 ago) Posting: # 21977 Views: 611 

Hi all., can any one explain difference between Linear and Nonlinear pharmacokinetics. if drugs exist Nonlinear pharmacokinetics which study design likely to choose. Please help me. regards, sridhar Edit: Category changed; see also this post #1. [Helmut] 
ElMaestro ★★★ Belgium?, 20201008 11:13 (50 d 09:32 ago) @ Sridhar.E Posting: # 21982 Views: 569 

Hi Sridhar.e, » can any one explain difference between Linear and Nonlinear pharmacokinetics. In practice: If Cmax or AUC or Clearance scales linear with the ingested dose, then kinetics is linear. For example, if the Cmax is 50 ng/mL at a dose of 100 mg, and it is 100 ng/mL at a dose of 200 mg, then it would seem linear at least in that interval. This mainly has bearings on the dose you might need to apply in your BE trial if you wish to apply for waivers of some strengths. The design used for a linear drug is not necessarily different from the design used for a nonlinear drug. If the drug displays a morethanproportional trace of Cmax (or AUC or CL) versus dose, then a dose at the upper end may be more discriminative. And vice versa. Don't get bogged down by the discussion of terminology; linearity vs proportionality. I believe it is not particularly difficult to find people who happily spend hours on it. Just let them. Finding out if a drug is linear is sometimes tricky. Often such ADME behaviour can be looked up on SPC's or prescr. info but if you need to study the phenomenon yourself then this is a pretty troublesome affair. — I could be wrong, but... Best regards, ElMaestro No, of course you do not need to audit your CRO if it was inspected in 1968 by the agency of Crabongostan. 
Sridhar.E ☆ India, 20201008 11:23 (50 d 09:22 ago) @ ElMaestro Posting: # 21983 Views: 563 

Thank you for your valuable suggestion, the information you provided really helped me a lot. Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut] 
Helmut ★★★ Vienna, Austria, 20201008 11:44 (50 d 09:02 ago) @ Sridhar.E Posting: # 21984 Views: 563 

Hi Sridhar, » can any one explain difference between Linear and Nonlinear pharmacokinetics. Linear PK means that bioavailability is – strictly – proportional to the dose, e.g., if you double the dose, the AUC will double as well. The EMA accepts data from reliable sources (peerreviewed journals, PARs, SmPCs). If the the ratio of dosenormalized AUCs is within 75–125%, fine. If you have no data, perform a higherorder crossover study and fit the „power model”$$AUC=\alpha\cdot Dose^{\, \beta}\tag{1}$$Since \((1)\) requires software for nonlinear modelling, most people opt for the linearized alternative $$\log_{e}AUC=\log_{e}\alpha+ \beta \cdot \log_{e}Dose \tag{2}$$ and assess the confidence interval of \(\beta\). For some examples see the vignette of the package PowerTOST . Note that the acceptance range of the CI depends on the ratio of the highest/lowest dose. Hence, to demonstrate dose proportionality you will need a larger sample size for an increasing dose range.Types of nonlinear PK
» if drugs exist Nonlinear pharmacokinetics which study design likely to choose. To show what? — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
martin ★★ Austria, 20201016 06:34 (42 d 14:11 ago) @ Sridhar.E Posting: # 22012 Views: 397 

dear sridhar, Some hopefully helpful thoughts on linear/nonlinear PK are also given here Assessing goodness‐of‐fit for evaluation of dose‐proportionality which you may find of interest. hope this helps martin 
Helmut ★★★ Vienna, Austria, 20201016 13:38 (42 d 07:08 ago) @ martin Posting: # 22018 Views: 372 

Hi Martin, » […] Assessing goodness‐of‐fit for evaluation of dose‐proportionality 10 (ten!) authors, six of them members of the forum. — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 