Nonlinear PK (less than proportional increase in AUC): lowest strength [Design Issues]

posted by Helmut Homepage – Vienna, Austria, 2018-05-17 12:11  – Posting: # 18773
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Hi Lakshimi,

» As per canadian guidelines the fasting and fed study was required for only modified formulations.

It still is! Comparative Bioavailability Standards: Formulations Used for Systemic Effects, Section 2.1.1.1 (2012):

Requirements for modified-release dosage forms differ from those for immediate-release formulations because a greater likelihood exists that increased inter-subject variability in bioavailability will occur, including the possibility of dose-dumping. There may also be an increased risk of adverse effects such as gastrointestinal irritation, depending on the site of drug release, or absorption, or both. Hence, for all modified-release dosage forms (including delayed-release formulations), bioequivalence should be demonstrated under both fasted and fed conditions.


» So, I think we can go with fasting study …

Correct, since the tablets are IR.

» … and I was checked literature i didnt find any non-linear things in kinetics.

Maybe you should improve your skills in literature research.1–5
Click here ⇒  :google: or there ⇒ Google Scholar

HC’s guidance, section 2.1.1.3:

For drugs with non-linear pharmacokinetics in the single unit dose range of approved strengths due to saturable absorption and resulting in less than proportional increases in AUC with increasing dose, the comparative bioavailability study should be conducted on at least the lowest strength (single dose unit).



  1. Brittain DC, Scully BE, Hirose T, Neu HC. The pharmacokinetic and bactericidal characteristics of oral cefixime. Clin Pharmacol Ther. 1985;38(5):590-4. doi:10.1038/clpt.1985.229.
  2. Faulkner RD, Fernandez P, Lawrence G, Sia LL, Falkowski AJ, Weiss AI, Yacobi A, Silber BM. Absolute bio­availability of cefixime in man. J Clin Pharmacol. 1988;28(8):700-6. doi:10.1002/j.1552-4604.1988.tb03203.x.
  3. Guay DRP, Meatherall RC, Harding GK, Brown GR. Pharmacokinetics of Cefixime (CL 284,635; FK 027) in Healthy Subjects and Patients with Renal Insufficiency. Antimicrob Agents Chemother. 1986;30:485–90. [image] free resource.
  4. Klepser ME, Marangos MN, Patel KB, Nicolau DP, Quintiliani R, Nightingale C. Clinical Pharmacokinetics of Newer Cephalosporins. Clin Pharmacokin. 1995;28(5):361–384. doi:10.2165/00003088-199528050-00003.
  5. Nix DE, Symonds WT, Hyatt JM, Wilton JH, Teal MA, Reidenberg P, Affrime MB. Comparative Pharmaco­kinetics of Oral Ceftibuten, Cefixime, Cefaclor, and Cefuroxime Axetil in Healthy Volunteers. Pharmacother. 1997;17(1):121–5. doi:10.1002/j.1875-9114.1997.tb03684.x.

Cheers,
Helmut Schütz
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