Transcript Guidelines

WHO Workshop on Assessment of
Bioequivalence Data
Addis Ababa, 31. August – 3. September 2010
Artemisinin-based Products
Dr. Henrike Potthast ([email protected])
WHO Workshop on Assessment of Bioequivalence Data, Addis Ababa, 31. August – 3. September 2010
Arte Drugs
 Multisource drugs should be safe and effective
alternatives to brand name prescriptions, i.e.
interchangeable
 Multisource drugs can help to reduce cost of prescription
drugs
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
TABLE 2. Parametric 90% CIs for the mean pharmacokinetic properties of
dihydroartemisinin and piperaquine after the administration of a single oral dose of
Arterakine and Artekin (reference formulation)
Drug and parameter
Dihydroartemisinin
Cmax
AUC0-last
AUCextr
Cmax/AUCextr
Arterakine/Artekin
point estimator (%)
136.4
122.0
121.6
105.9
a Determined by using log-transformed data.
b Value falls outside the range of 80 to 125%.
Chinh et al, 2009
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
90% CIa
100.6–152.8b
105.4–137.3b
105.0–137.3b
92.9–114.8
Arte Drugs
Conclusion according to Chinh et al., 2009
 “Although the lower contents of dihydroartemisinin (8%)
and piperaquine (1.8%) in the Artekin than in the
Arterakine tablets would have contributed to the
bioinequivalence of the two formulations, after adjustment
for drug content, the Cmax and AUC of both drugs were
still outside the acceptance range of 80 to 125% (data
not shown). …………... Because the bioavailability of
dihydroartemisinin and piperaquine was only marginally
higher after Arterakine than after Artekin administration,
the two formulations are expected to result in similar
therapeutic efficacies in the treatment of malaria
infections.”
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
 Artemisinin…
 …has low bioavailability after oral administration probably
due to incomplete absorption, tmax occurs approx. 2 to 3
hours postdose; elimination is rapid (t1/2ß: 2 to 3 hours)
Decline of plasma concentrations has been observed
following repeated administration, hence it is has been
considered likely that artemisinin induces its own
breakdown (time-dependent PK)…...
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
 Artesunate…
 …is water-soluble but a slow dissolving drug
substance. … “e.g approx. 55% of artesunate are released in
45 minutes.”
“The in vivo pharmacokinetic characteristics of the
molecule are complex. …. The parent drug artesunate is
difficult to be used for pharmacokinetic measures since it
is metabolised rapidly into dihydroartemisinin (DHA) …...
the global biopharmaceutical picture for artesunate and
DHA is extremely complex …...”
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
 Artesunate…
 …is a prodrug of dihydroartemisinin.
“…However, since the bioavailability of oral artesunate
probably depends on dissolution in the gastrointestinal tract
and intraluminal conversion to dihydroartemisinin,
physicochemical (pharmaceutical) interactions should be
taken into consideration ….” (Giao et al. Clin Pharmacokinet. 40, 2001)
 After repeated administration dihydroartemisinin
concentrations decline.
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
 Dihydroartemisinin…
 …is not water-soluble.
The in vivo pharmacokinetic characteristics are mostly
known from studies with artemether or artesunate; its
bioavailability is greater than that of artemisinin …...
According to Jansen, Malaria J.9, 2010, it seems that there are
relevant problems with pharmaceutical quality (namely stability) with
respective formulations.
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
 Artemether…
 …is a lipid-soluble derivative of artemisinin.
It is rel. rapidly absorbed (tmax after approx. 2 hours) and
undergoes extensive first-pass metabolism to
dihydroartemisinin.
 After repeated dose artemether Cmax declines while
dihydroartemisinin concentrations increase.
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
 add. example Mefloquine…
 …hydrochloride is a fast dissolving drug substance. ….
But in vivo the drug is absorbed slowly. ….and has t1/2ß
ranging from 14 to 22 days…pharmacokinetics are highly
stereoselective …... and may be formulationdependent …...food increases bioavailability
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
 add. example Lumefantrine…
 …is a highly lipophilic drug substance. ….
Its absorption in vivo is rather slow with low and variable
bioavailability (tmax approx. 10h). ….the reported t1/2ß
ranges from 33 hours to 6 …...food increases
bioavailability
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
What should be considered?
 Comparator product
 In vitro dissolution rel. easy – but sufficient?
 Pro-drug, or active drug, or metabolite
 Long half-life – AUCt??
 Food-effects
 Interpretation of in-equivalence
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
 http://apps.who.int/prequal/
Guidance Document 22 June 2009
Recommended comparator products: anti-malarial
medicines
„Comparator products should be purchased from a well regulated
market with stringent regulatory authority i.e., from countries
participating in the International Conference on Harmonization
(ICH)∗.“
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
What should be considered?
 Comparator product
 In vitro dissolution rel. easy – but sufficient?
 Pro-drug, or active drug, or metabolite
 Long half-life – AUCt??
 Food-effects
 Interpretation of in-equivalence
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
What should be considered?
 Comparator product
 In vitro dissolution rel. easy – but sufficient?
 Pro-drug, or active drug, or metabolite
 Long half-life – AUCt??
 Food-effects
 Interpretation of in-equivalence
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
 Options from the PQP
 “Given the difficulties associated with collecting
bioequivalence data with this product, the program
suggests that the applicant employ one of the two
following options:….”
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
 Options from the PQP ctd:
 1. It is recommended that your Artequin artesunate
50mg/mefloquine 125mg product be compared to the appropriate
program comparator products in a single dose, crossover
comparative bioavailability study conducted in healthy adult
volunteers under fed conditions i.e., drug administration should take
place following completion of a standard breakfast, not a high-fat,
high-calorie meal, as a standard breakfast is considered to be
closest to real life conditions in malaria patients. The following
doses can be administered:
– Treatment A: 2 x test (artesunate / mefloquine)
– Treatment B: 2 x artesunate (from Arsuamoon) + 1 x Lariam
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
 Options from the PQP ctd:
 Ad 1. “... a wash-out period of 15 weeks be employed for this study
and that the number of subjects employed in the study be adjusted
slightly to account for higher than usual subject dropouts. With
regard to artesunate, it is recommended that both the parent
compound, artesunate, and the primary active metabolite,
dihydroartemisinin (DHA), be monitored during the study. ….. . it
is recommended that both analytes be monitored and the program
will evaluate the total data package as appropriate. ….. the study
should be powered based on artesunate. ……. blood sample
collection in the study need not continue past 72 hours post-dose….”
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
 Options from the PQP ctd:
 2. “Alternatively, it is recommended that two
bioequivalence studies be undertaken to demonstrate the
safety and efficacy of the proposed product:
– A. An appropriately designed single dose, crossover comparative
bioavailability study conducted in healthy adult volunteers
intended to establish the bioequivalence of the artesunate
component of the proposed product.”
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
 Options from the PQP ctd:
plus
– “B. An appropriately designed single-dose, parallel comparative
bioavailability study conducted in healthy adult volunteers
intended to establish the bioequivalence of the mefloquine
component of the proposed product. This study should be
conducted under fed conditions i.e., drug administration should
take place following completion of a standard breakfast, not a
high-fat, high-calorie meal, as a standard breakfast is considered
to be closest to real life conditions in malaria patients.”
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
Arte Drugs
THANK YOU
FOR YOUR ATTENTION
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WHO Workshop on Assessment Bioequivalence Data
31. August – 3. September 2010, Addis Ababa