HVDs/HVDPs = safe drugs [Off Topic]
Hi Ken,
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.
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.
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.
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:
❝ […] 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.
- If that would not be the case, the innovator would not have been able to demonstrate safety / efficacy in the phase III trials. The product would not have been approved.
- The innovator’s product is on the market for many years – “surviving” phase IV, the close pharmacovigilance program in the first years, and AE monitoring/reporting.
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)- 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.
- 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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Helmut Schütz
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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
Complete thread:
- effectiveness of highly variable drugs Ken Peh 2013-12-17 03:45 [Off Topic]
- HVDs/HVDPs = safe drugsHelmut 2013-12-17 15:11
- HVDs/HVDPs = safe drugs varun9461 2019-02-22 12:23
- effectiveness of highly variable drugs Dr_Dan 2013-12-18 09:34
- effectiveness of highly variable drugs Ohlbe 2013-12-18 10:07
- effectiveness of highly variable drugs Ken Peh 2013-12-20 14:38
- Period effect kumarnaidu 2014-01-28 07:54
- Period effect Dr_Dan 2014-01-28 10:36
- Period effect kumarnaidu 2014-01-28 11:51
- Period effect Helmut 2014-01-28 13:48
- Period effect kumarnaidu 2014-01-29 04:49
- Period effect Helmut 2014-01-28 13:48
- Period effect kumarnaidu 2014-01-28 11:51
- Period effect Dr_Dan 2014-01-28 10:36
- Period effect kumarnaidu 2014-01-28 07:54
- effectiveness of highly variable drugs Ken Peh 2013-12-20 14:38
- effectiveness of highly variable drugs Ohlbe 2013-12-18 10:07
- HVDs/HVDPs = safe drugsHelmut 2013-12-17 15:11