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!