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International Congress of Chemotherapy

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Presentation on theme: "International Congress of Chemotherapy"— Presentation transcript:

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
Drug Chemical compound Half life (t 1/2) Chloroquine 4 – aminoquinoline 10 days Amodiaquine 4 - aminoquinoline 10 hrs Sulfa-Pyrim Antifolate: dhfs, dhps 8 days (Sulfa); 4 days (Pyr) Proguanil antifolate: dhfs prophylactic agent + CQ 16 hrs Quinine, Quinidine Quinoline extracted from the Peruvian cinchona tree hrs Mefloquine arylaminoalcohol days Halofantrine Phenantrine methanol (lumefantrine) 1 - 6 days Artemisinin derivatives derived from Chinese plant Artemesia annua hrs (DHA: hrs) TCN, DCN Antibiotics + Quinine TCN: 8 hrs, DCN hrs WHO/CDS/RBM/

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

4 In vivo pharmacodynamics
Antimalarial drugs Estimated PRR in vivo Artemisinin derivatives 1,000-10,000 4-aminoquinolines, halofantrine Quinine, mefloquine, SP Antimalarial antibiotics 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):

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 In high transmission areas with multiple inoculations (green arrows) …..
White NJ. Antimocrobial Agents and Chemotherapy, 1997; 41 (7):

8 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:

9 White NJ. Antimalarial drug resistance. J of Clin Invest

10 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 ++++ The slowly eliminated antimalarial such as CQ or MEF presents a lengthy opportunity for the selection of resistance among sensitive parasites (MIC A), but once resistance has become established (MIC B), the terminal elimination phase is no longer selective, because the blood concentrations are no longer inhibitory. ART CQ MEF White NJ. Antimalarial drug resistance. J of Clin Invest., 2004 ; 113(8):

11 Source: WHO, 2000

12 Geographical Distribution of Malaria in the Philippines
(Based on 10-year Ave, ) 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

13 GEOGRAPHICAL DISTRIBUTION OF MALARIA CASES PHILIPPINES, 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

14 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 : Palawan % % 2000: Kalinga/Apayao % % 2000: DavaoNorte/ComVal % % : Agusan del Sur % % * TES: 28-day therapeutic efficacy studies (all ages)

15 Sequential vs simultaneous treatment with CQ+SP in P
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+SP4 CQ+SP0 Sample size (n) Age (yrs) Weight (kg) Parasitemia (cumm) , ,876 PCT (hrs) FCT (hrs) parasite t1/2 (hrs) p=0.006

16 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): ) CQ + SP4 CQ + SP0 Cmax CQ 285 ng/ml Cmax CQ ng/ml DCQ DCQ 220 AUC CQ day ng/ml AUC CQ day ng/ml DCQ DCQ 2680

17 Chloroquine 3 days + SP single dose on Day 4
Cmax (ng/ml) CQ DCQ AUC (day ng/ml) CQ DCQ T ½ (days) CQ DCQ

18 Chloroquine 3 days + SP single dose on Day 0
Cmax (ng/ml) CQ DCQ Sulfa Pyrim AUC (day ng/ml) CQ DCQ Sulfa Pyrim T ½ (days) CQ DCQ Sulfa Pyrim

19 Sequential vs simultaneous treatment with CQ+SP in Pf malaria in the Philippines
PCT (hrs) FCT (hrs) parasite t1/2 (hrs) (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

20 New Malaria Drug Policy AO. 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

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

22 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

23 THANK YOU!


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