Transcript The pharmacokinetics and pharmacodynamics of antimalarials

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
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
10 - 12 hrs
Peruvian cinchona tree
Mefloquine
arylaminoalcohol
10 - 40 days
Halofantrine
Phenantrine methanol
(lumefantrine)
1 - 6 days
Artemisinin
derivatives
derived from Chinese plant
Artemesia annua
4 - 11 hrs (DHA: 11 - 12 hrs)
TCN, DCN
Antibiotics + Quinine
TCN: 8 hrs, DCN 14 - 24 hrs
WHO/CDS/RBM/2001.33
Pharmacokinetic properties of generally
available anti-malarial drugs
White NJ. Antimalarial drug resistance. J of Clin Invest., 2004 ; 113(8): 1084-1092
In vivo pharmacodynamics
Antimalarial drugs
Artemisinin derivatives
4-aminoquinolines, halofantrine
Quinine, mefloquine, SP
Antimalarial antibiotics
Estimated PRR in vivo
1,000-10,000
100-1000
10-100
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
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
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
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
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
P h ilip p in e s
In c i d e n c e o f c o n fi r m e d m a la r i a
(p e r 1 0 0 0 ) , 2 0 0 0
0 .0 0 1 - 0 .5
0 .5 - 1
1 - 5
5 - 10
10 - 20
20 - 50
N o t a v a i l a b le o r z e ro
Source: WHO, 2000
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
GEOGRAPHICAL DISTRIBUTION OF MALARIA CASES
PHILIPPINES, 2003
Category A Provinces
• 9 provinces
• More than 1000 cases
Manila
Category B Provinces
• 20 provinces
• 100 to 1000 cases
Category C Provinces
• 18 provinces
• less than 100 cases
Category D Provinces
• 31 provinces
• No reported cases
History of Chloroquine and SulfadoxinePyrimethamine 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):
1995-1999: Palawan
2000: Kalinga/Apayao
2000: DavaoNorte/ComVal
1997-2001: Agusan del Sur
CQ
SP
43-59%
49%
55%
18-49%
21%
9%
49%
53%
* TES: 28-day therapeutic efficacy studies (all ages)
Sequential vs simultaneous treatment with CQ+SP
in P. falciparum malaria in the Philippines


CQ+SP4 :
CQ+SP0 :
CQ 3 days + SP on Day 4
CQ 3 days + SP on Day 0
CQ+SP4
Sample size (n)
Age (yrs)
Weight (kg)
Parasitemia (cumm)
PCT (hrs)
FCT (hrs)
parasite t1/2 (hrs)
11
25
60
13,284
48
34
5.7
CQ+SP0
21
32
52
18,876
39
24
2.5
p=0.006
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
Cmax CQ
DCQ
AUC CQ
DCQ
285 ng/ml
89
2299 day ng/ml
1845
CQ + SP0
Cmax CQ
DCQ
AUC CQ
DCQ
283 ng/ml
220
1980 day ng/ml
2680
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
DCQ
5.7
7.3
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
DCQ
Sulfa
Pyrim
5.9
8.5
10.9
2.9
Sequential vs simultaneous treatment with CQ+SP in Pf malaria in the Philippines
CQ + SP4
PCT (hrs)
FCT (hrs)
parasite t1/2 (hrs)
CQ + SP0
48
34
5.7
39
24
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
New Malaria Drug Policy
AO. 129 s. 2002, MCP- DOH
“Old” Drug Policy
New Drug Policy
1st line: Chloroquine
1st line: CQ+SP
2nd line: SulfadoxinePyrimethamine (SP)
3rd line: Quinine
2nd line: Artemether +
lumefantrine (Coartem™)
3rd line: Quinine + antibiotic (TCN, Doxycyline,
Clindamycin)
+ Primaquine
+ Primaquine
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)
 Palawan, 1995
CQ+SP
CQ+SP
70% ACPR
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
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
THANK YOU!