HVDs/HVDPs = safe drugs [Off Topic]

posted by Helmut Homepage – Vienna, Austria, 2013-12-17 15:11 (2427 d 15:38 ago) – Posting: # 12069
Views: 10,630

Hi Ken,

» […] I was stunned when asked by a cardiologist what contributed to the high variability from the same product.

First we have to distinguish between Highly Variable Drugs (HVDs) and Highly Variable Drug Products (HVDPs). The former show a CVintra >30% if administered as a solution in a replicate design. It might well be that a drug shows low variability as a solution, but high variability if administered in a particular formulation. Example: CV of a diclofenac solution is <10%, some gastric resistant products are HVDPs, and all topical products I have seen so far.

» Absorption, metabolism etc?

See the basic equation of PK: AUC = F×D/CL. If we assume that the dose is identical across administra­tions, both absorption (F) and elimination (CL) can contribute to variability. Think about LADME. If we administer a solution we remove only the liberation part of the game. So even then we don’t know whether absorption (i.e., permeation/transport), DME, or all of it causes the high variability. Only if we would administer the drug repeatedly IV, we could exclude absorption as a cause.

» Should highly variable drugs be used in clinical practice ??

Why not? HVDs/HVDPs are both safe and efficacious despite their high variability – they have flat dose-response curves. On the other hand, NTI drugs are never highly variable.Coming back to clopidogrel: Its high variability is mainly caused by both presystemic and first-pass meta­bolism. Thhe EMA in its Q&A-document do not recommend reference-scaling based on unclear clinical implications. Don’t know what USFDA’s current thinking is. The product-specific guidance is quite old (08/2008) and was issued before RSABE first appeared as an option (04/2010). The FDA generally does not require a clinical justification (contrary to the EMA) and allows scaling for both AUC and Cmax.

Another option to tackle HVDs/HVDPs (if the variability is caused by CL) in BE would be stable isotopes in a conventional 2×2 crossover. If we administer in both periods simultaneously to the oral products a small dose of a stable isotope IV, we can calculate the clearance on both occasions and – instead of assuming constant clearances – plug in the true values. In many cases the reduction in variability is tremendous. This method was fashionable in the 1980s, but was rarely used in the more recent past, since the IV-formulation has to be compliant with cGMPs. Interestingly it is mentioned in Japanese guidances. For details see Parr et al. (2012)¹ and a quote from Polli et al. (2012)²:

The application of the stable isotope approach as an aid to set product specifications, in bioequivalence studies, and evaluation of QbD design space has been discussed with relevant groups at the FDA as a proposal. The proposal was received positively by the agency and the application of the approach to a specific example was encouraged.

(my emphases)


  1. Parr A, Gupta M, Montague TH, Hoke F.[/b] Re-introduction of a Novel Approach to the Use of Stable Isotopes in Pharmacokinetic Studies. AAPS J. 2012;14(3):639–45. doi:10.1208/s12248-012-9371-4.
  2. Polli JE, Cook JA, Davit BM, Dickinson PA, Argenti D, Barbour N, García-Arieta A, Geoffroy J-M, Hartauer K, Li S, Mitra A, Muller FX, Purohit V, Sanchez-Felix M, Skoug JW, Tang K. Summary Workshop Report: Facilitating Oral Product Development and Reducing Regulatory Burden Through Novel Approaches to Assess Bioavailability/Bioequivalence. AAPS J. 2012;14(3):627–38. doi:10.1208/s12248-012-9376-z.

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