1. WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, 31. August – 3. September 2010 Artemisinin-based Products Dr. Henrike Potthast (henrike.potthast@bfarm.de) WHO Workshop on Assessment of Bioequivalence Data, Addis Ababa, 31. August – 3. September 2010

2. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 2 |2 | 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

3. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 3 |3 | Arte Drugs Chinh et al, 2009 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 Arterakine/Artekin 90% CIa point estimator (%) Dihydroartemisinin Cmax 136.4 100.6–152.8b AUC0-last 122.0 105.4–137.3b AUCextr 121.6 105.0–137.3b Cmax/AUCextr 105.9 92.9–114.8 a Determined by using log-transformed data. b Value falls outside the range of 80 to 125%.

4. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 4 |4 | 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.”

5. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 5 |5 | 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)…...

6. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 6 |6 | 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 …...”

7. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 7 |7 | 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.

8. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 8 |8 | 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.

9. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 9 |9 | 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.

10. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 10 | 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 formulation- dependent …...food increases bioavailability

11. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 11 | 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

12. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 12 | 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

13. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 13 | 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) ∗.“

14. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 14 | 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

15. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 15 | Arte Drugs

16. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 16 | 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

17. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 17 | 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:….”

18. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 18 | 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

19. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 19 | 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….”

20. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 20 | 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.”

21. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 21 | 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.”

22. WHO Workshop on Assessment Bioequivalence Data 31. August – 3. September 2010, Addis Ababa 22 | Arte Drugs THANK YOU FOR YOUR ATTENTION