Ma. Dorina G. Bustos, MD, PhD Research Institute for Tropical Medicine Department of Health

1. International Congress of Chemotherapy Manila, 4-6 June 2005 ISAP Symposium The pharmacokinetics and pharmacodynamics of antimalarials: a new approach in the treatment of malaria, the Philippine experience Ma. Dorina G. Bustos, MD, PhD Research Institute for Tropical Medicine Department of Health Philippines

2. The Antimalarial Repertoire WHO/CDS/RBM/2001.33

3. Pharmacokinetic properties of generally available anti-malarial drugs White NJ. Antimalarial drug resistance. J of Clin Invest., 2004 ; 113(8): 1084-1092

4. In vivo pharmacodynamics Antimalarial drugs Estimated PRR in vivo Artemisinin derivatives 1,000-10,000 4-aminoquinolines, halofantrine 100-1000 Quinine, mefloquine, SP 10-100 Antimalarial antibiotics 5 - 10 PRR = parasite reduction ratio: baseline parasite count/parasite count 48 hours later: this rises if there is background immunity and falls with resistance

5. Pharmacodynamics: parasite reductions produced by different antimalarial drugs PRR: Fractional reduction per asexual cycle vary from < 10 (antibiotics with antimalarial activity and antimalarials for which high level drug resistance exist) to 10,000 (artemisinin derivatives). White NJ. Antimocrobial Agents and Chemotherapy, 1997; 41 (7): 1413-1422

6. Parasite stage specific activity varies between compounds • DHFR inhibitors – narrow window of activity on 2nd half of parasite life cycle • Quinine, mefloquine – wide time window but only on 2nd half of life cycle • Chloroquine and halofantrine - wider time window on circulating forms • Artemisinins – broadest range of all, with considerable effect on ring stages and early immature gametocyte stage

7. The dose-response curve in malaria. • Increasing drug resistance leads to a rightward shift in the dose- response • or concentration effect relationship. • The principal effect in uncomplicated malaria is parasite killing. White NJ. Trends in Parasitology, 2002: 18: 458-464

8. Antimalarial Pharmacokinetics and Resistance Drug characteristics that may select for resistance: • Poor oral bioavailability with wide range in blood levels • Drugs with long terminal elimination half life ART CQ MEF White NJ. Antimalarial drug resistance. J of Clin Invest., 2004 ; 113(8): 1084-1092

9. Source: WHO, 2000

10. Geographical Distribution of Malaria in the Philippines (Based on 10-year Ave, 1991 -2000) • Category A Provinces • 25 Provinces • more than 1000 cases/year • or situation worsened • Category B Provinces • 22 Provinces • 100 to 1000 cases/year • Category C Provinces • 18 Provinces • less than 100 cases/year • Category D Provinces • Provinces that are already • malaria-free (no more • indigenous cases for • at least 3 years) Source: Malaria Control Program, 2000

11. GEOGRAPHICAL DISTRIBUTION OF MALARIA CASESPHILIPPINES, 2003 • Category A Provinces • 9 provinces • More than 1000 cases • Category B Provinces • 20 provinces • 100 to 1000 cases Manila • Category C Provinces • 18 provinces • less than 100 cases • Category D Provinces • 31 provinces • No reported cases

12. History of Chloroquine and Sulfadoxine- Pyrimethamine Resistance in the Philippines • CQ or AQ has been the first line drug since the 1950s • SP introduced as second line drug in the mid 80s • CQ resistance reported as early as 1969, and SP in 1990s • Therapeutic failures (TES): CQ SP • 1995-1999: Palawan 43-59% 21% • 2000: Kalinga/Apayao 49% 9% • 2000: DavaoNorte/ComVal 55% 49% • 1997-2001: Agusan del Sur 18-49% 53% • * TES: 28-day therapeutic efficacy studies (all ages)

13. Sequential vs simultaneous treatment with CQ+SP in P. falciparum malaria in the Philippines • CQ+SP4 : CQ 3 days + SP on Day 4 • CQ+SP0 : CQ 3 days + SP on Day 0 CQ+SP4CQ+SP0 Sample size (n) 11 21 Age (yrs) 25 32 Weight (kg) 60 52 Parasitemia (cumm) 13,284 18,876 PCT (hrs) 48 39 FCT (hrs) 34 24 parasite t1/2 (hrs) 5.7 2.5 p=0.006

14. Sequential vs simultaneous treatment with CQ+SP in Pf malaria in the Philippines (Bustos et al, Tropical Med and Int’l Health, 2002; 7(7): 584-591) CQ + SP4 CQ + SP0 Cmax CQ 285 ng/ml Cmax CQ 283 ng/ml DCQ 89 DCQ 220 AUC CQ 2299 day ng/ml AUC CQ 1980 day ng/ml DCQ 1845 DCQ 2680

15. Chloroquine 3 days + SP single dose on Day 4 Cmax (ng/ml) CQ 285 DCQ 89 AUC (day ng/ml) CQ 2299 DCQ 1845 T ½ (days) CQ 5.7 DCQ 7.3

16. Chloroquine 3 days + SP single dose on Day 0 Cmax (ng/ml) CQ 283 DCQ 220 Sulfa 169 Pyrim 591 AUC (day ng/ml) CQ 1980 DCQ 2680 Sulfa 2757 Pyrim 3029 T ½ (days) CQ 5.9 DCQ 8.5 Sulfa 10.9 Pyrim 2.9

17. Sequential vs simultaneous treatment with CQ+SP in Pf malaria in the Philippines CQ + SP4 CQ + SP0 PCT (hrs) 48 39 FCT (hrs) 34 24 parasite t1/2 (hrs) 5.7 2.5 (p=0.006) Parasite elimination half-life (t1/2): determined by linear regression from its maximum peak to zero, maybe a better indicator of the rate of complete parasite reduction

18. New Malaria Drug PolicyAO. 129 s. 2002, MCP- DOH “Old” Drug Policy 1st line: Chloroquine 2nd line: Sulfadoxine-Pyrimethamine (SP) 3rd line: Quinine + Primaquine New Drug Policy 1st line:CQ+SP 2nd line:Artemether + lumefantrine (Coartem™) 3rd line: Quinine + anti- biotic (TCN, Doxycyline, Clindamycin) + Primaquine

19. CQ+SP and AL (Coartem™) efficacy in selected study sites, Philippines, 2001-2004 • Kalinga & Isabela, 2004 CQ+SP 94% ACPR AL 99% ACPR • Bulacan, 2002 (outbreak > 6 mos) CQ+SP 70% ACPR • Palawan, 1995 CQ+SP 88% ACPR On-going TES, 2005 • Com Val & ADS, 2001 CQ+SP 82% ACPR AL 100% ACPR On-going TES, 2005 ACPR: Adequate Clinical and Parasitological Response

20. Acknowledgements • Malaria Study Group, Research Institute for Tropical Medicine (RITM), Department of Health, Alabang • Infectious Disease Office, Department of Health, Manila • Essential National Health Research, DOH • Partners: French government, Hopital Pitie-Salpetriere, Paris, France; WHO/RBM, US CDC, USAID, US NAMRU2, Global Fund, AusAID • Pharmaceutical Industries

21. THANK YOU!