Ken Peh
★    

Malaysia,
2013-12-17 03:45

Posting: # 12066
Views: 10,550
 

 effectiveness of highly variable drugs [Off Topic]

Dear Friends,

This is an off topic question.
We conducted BE studies on a highly variable drug, clopidogrel, a generic versus Plavix. The same subject who was dosed twice with the same product (irrespective of generic or comparator) showed drastic difference in AUC and Cmax. I was stunned when asked by a cardiologist what contributed to the high variability from the same product. Absorption, metabolism etc :confused:?

Should highly variable drugs be used in clinical practice ??

Thank you for your kind sharing.

Regards,
Ken
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2013-12-17 15:11

@ Ken Peh
Posting: # 12069
Views: 9,735
 

 HVDs/HVDPs = safe drugs

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.
  • 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.
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.

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
varun9461
☆    

India,
2019-02-22 12:23

@ Helmut
Posting: # 19966
Views: 2,032
 

 HVDs/HVDPs = safe drugs

» Coming back to clopidogrel: Its high variability is mainly caused by both presystemic and first-pass meta­bolism. The 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.

Question: wrt to EMA Q&A about clopidogrel not allowing widening on CMAX, can we plan full replicate BE study with BE Limit of 80.00-125.00% or two way cross over BE study needs to be performed?


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). Standard quotes restored (see in the same post #8). Please follow the Forum’s Policy[Helmut]
Dr_Dan
★★  

2013-12-18 09:34

@ Ken Peh
Posting: # 12070
Views: 9,507
 

 effectiveness of highly variable drugs

Dear Ken
Please keep in mind that the active metabolite of clopidogrel which was demonstrated to be linearly related to the AUC of clopidogrel is not as variable as the parent drug and within the systemic circulation the active metabolite is about 5000-fold higher than the inactive parent drug. In consequence high variability in PK parameters of the parent drug do not necessarily lead to high variability in therapeutic outcome. The limiting step for maximal effect of clopidogrel is not bioavailability but biotransformation (see Savi P, Herbert JM: Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost. 2005; 31: 174-83).
Kind regards
Dan

Kind regards and have a nice day
Dr_Dan
Ohlbe
★★★

France,
2013-12-18 10:07

@ Dr_Dan
Posting: # 12071
Views: 9,632
 

 effectiveness of highly variable drugs

Dear Dan,

» [...] within the systemic circulation the active metabolite is about 5000-fold higher than the inactive parent drug.

I had figures in mind of about 2000-fold for the inactive carboxyacid metabolite. The few papers I have seen where the active thiol metabolite (H4) was measured indicate (on a limited population, after repeated administration) a much lower Cmax ratio. I didn't see any information on intra-CV of this metabolite (but I only browsed very quickly through the papers, and did not do an extensive review of litterature).

See these papers for more info:
Makoto Takahashi, Henrianna Pang, Kiyoshi Kawabata, Nagy A. Farid, Atsushi Kurihara
Quantitative determination of clopidogrel active metabolite in human plasma by LC–MS/MS
Journal of Pharmaceutical and Biomedical Analysis 48 (2008) 1219–1224

Marta Karazniewicz-Łada, Dorota Danielak, Artur Tezyk, Czesław Zaba, Gilles Tuffal, Franciszek Główka
HPLC–MS/MS method for the simultaneous determination of clopidogrel, its carboxylic acid metabolite and derivatized isomers of thiol metabolite in clinical samples
Journal of Chromatography B, 911 (2012) 105– 112

Michael T. Furlong, Ishani Savant, Moucun Yuan, Laura Scott, William Mylott, Thomas Mariannino, Pathanjali Kadiyala, Vikram Roongta, Mark E. Arnold
A validated HPLC–MS/MS assay for quantifying unstable pharmacologically active metabolites of clopidogrel in human plasma: Application to a clinical pharmacokinetic study
Journal of Chromatography B, 926 (2013) 36– 41

Regards
Ohlbe
Ken Peh
★    

Malaysia,
2013-12-20 14:38

@ Ohlbe
Posting: # 12088
Views: 9,457
 

 effectiveness of highly variable drugs

Dear Helmut, Dr Dan and Ohlbe,

Thank you very much for your enlightening explanation and kind sharing.

Regards,
Ken
kumarnaidu
★    

Mumbai, India,
2014-01-28 07:54

@ Ken Peh
Posting: # 12280
Views: 9,045
 

 Period effect

Hi all,
If the the drug is highly variable then is it possible that we can get big difference in Cmax and AUC in two period for both test and reference. In one of pilot study I got the results below.

Test Cmax: Period 1 and period 2: 951 and 189 (approx)
Test AUC: Period 1 and period 2: 1700 and 225 (approx)

Reference Cmax: Period 1 and period 2: 830 and 276 (approx)
Reference AUC: Period 1 and period 2: 1500 and 360 (approx)


Edit: Subject line changed. [Helmut]

Kumar Naidu
Dr_Dan
★★  

2014-01-28 10:36

@ kumarnaidu
Posting: # 12281
Views: 9,094
 

 Period effect

Dear kumarnaidu
That's interesting. Why is the bioavailability much better in period 1 than in period 2 for both, test and reference? Systematic error? Artefact? What was the number of subjects and what was the CVintra?
Kind regards
Dan

Kind regards and have a nice day
Dr_Dan
kumarnaidu
★    

Mumbai, India,
2014-01-28 11:51

@ Dr_Dan
Posting: # 12282
Views: 9,132
 

 Period effect

Hi Dan,

» What was the number of subjects and what was the CVintra?

Here the number of subjects is 14. And Intrasubject CV for Cmax and AUCt is 29.8 and 33 respectively. This was a oral suspension.

Kumar Naidu
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2014-01-28 13:48

@ kumarnaidu
Posting: # 12283
Views: 9,088
 

 Period effect

Hi Kumar & Dan,

although it is interesting that you got only ~20–25% of period 1 in period 2, the behavior is consistent for both formulations and both PK metrics. The ratios are pretty close to 100%.

» This was a oral suspension.

So it might be worthwhile to look for an explanation (were the suspensions in both periods prepared in exactly the same way and by the same personnel?). However, the BE assess­ment and – since this is a pilot study – the estimated PEs and CVs are not affected. The period effect means out in a cross-over study.

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
kumarnaidu
★    

Mumbai, India,
2014-01-29 04:49

@ Helmut
Posting: # 12285
Views: 9,053
 

 Period effect

Thanks Dan and Helmut for your suggestions.

Kumar Naidu
Activity
 Admin contact
20,242 posts in 4,259 threads, 1,397 registered users;
online 7 (1 registered, 6 guests [including 3 identified bots]).
Forum time (Europe/Vienna): 07:17 CET

Operational hectic replaces
intellectual calms.    Alexander Huiskes

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5