Highly variable drugs

K. K. Midha, M. J. Rawson, and J. W. Huhban, Pre-scribability and switchability of highly variable drugs and drug products, J. Controlled Release, 62, 33 (1999). 

Absolute bioavailability this implies a comparison of plasma levels after oral and i.v. administration of the drug. Most psychotropic drugs have a good bioavailability, i.e. values between 30 and 100%. Low bioavailabilitv, as seen with buspirone, is associated with highly variable drug plasma concentrations and is not a desirable feature of a drug... 

Patterson SD, Zariffa NM, Montague TH, Howland K Nontraditional study designs to demonstrate average bioequivalence for highly variable drug products. Eur. J. Clin. Pharmacol. (2001) 57 663—670. 

Tothfalusi, L., Endrenyi, L., and Midha, K., Scaling or wider bioequivalence limits for highly variable drugs and for the special case of C(max), International Journal of Clinical Pharmacology and Therapeutics, Vol. 41, No. 5, 2003, pp. 217-225. 

Tothfalusi, L. and Endrenyi, L., Limits for the scaled average bioequivalence of highly variable drugs and drug products, Pharmaceutical Research, Vol. 20, No. 3, 2003, pp. 382-389. 

Patnaik, R.N. Lesko, L.J. Chen, M.L. Individual bioequivalence. New concepts in the statistical assessment of bioequivalence metrics. FDA individual bioequivalence working group. Clin. Pharmacokine. 1997, 33 (1), 1-6. Midha, K.K. Rawson, M.J. Hubbard, J.W. Individual and average bioequivalence of highly variable drugs and drug products. J. Pharm. Sci. 1997, 86 (11), 1193-1197. 

Tothfalusi L, et al. Evaluation of bioequivalence of highly variable drugs. Pharmaceutical Research, 2001, 18 728-733. 

Current Thinking Within the FDA for the Evaluation of Highly Variable Drugs and Drug Products... 

Haidar SH, Davit B, Chen ML, et al. Bioequivalence approaches for highly variable drugs and drag products. Pharm Res 2008 25(1) 237-241 [Epub September 22, 2007]. 

Benet LZ. Why highly variable drugs are safer. Meeting of FDA Committee for Pharmaceutical Science, October 6, 2006. Available at http //www.fda.gov/ohrms/dockets/ ac/06/slides/2006-4241s2 2 files/frame.htm. Accessed November 2007. 

The above results suggest that it is reasonable to expect that DDI would be detected using the population approach for drugs with low or moderate IIV, but very large sample sizes would be needed for high variability drugs. It is recommended that simulation study such as the one presented here be performed to support a claim of a lack of DDI. 

Highly variable drugs may require a far greater number of subjects to meet the FDA bioequivalence criteria. The variability seen in the performance of certain drug products may be due to the inherent characteristics of the drug or due to the drug formulation or both. 

Shah, P. et al., Evaluation of orally administered highly variable drugs and drug formulations, Pharm. Res., 13 1590-1595, 1996. 

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