Ma. Dorina G. Bustos, MD, PhDResearch Institute for Tropical Medicine

Department of HealthPhilippines

The pharmacokinetics and pharmacodynamics of antimalarials: a

new approach in the treatment of malaria, the Philippine experience

International Congress of ChemotherapyManila, 4-6 June 2005ISAP Symposium

The Antimalarial Repertoire

DrugDrug Chemical Chemical compoundcompound

Half life (Half life (t 1/2t 1/2))

ChloroquineChloroquine 4 – aminoquinoline4 – aminoquinoline 10 days10 daysAmodiaquineAmodiaquine 4 - aminoquinoline4 - aminoquinoline 10 hrs10 hrsSulfa-PyrimSulfa-Pyrim Antifolate: Antifolate: dhfs, dhpsdhfs, dhps 8 days (Sulfa); 4 days 8 days (Sulfa); 4 days

(Pyr)(Pyr)Proguanil Proguanil antifolate: antifolate: dhfs dhfs

prophylactic agent + CQprophylactic agent + CQ 16 hrs16 hrs

Quinine, Quinine, QuinidineQuinidine

Quinoline extracted from Quinoline extracted from the Peruvian cinchona the Peruvian cinchona treetree

10 - 12 hrs10 - 12 hrs

MefloquineMefloquine arylaminoalcoholarylaminoalcohol 10 - 40 days10 - 40 daysHalofantrineHalofantrine Phenantrine methanol Phenantrine methanol

(lumefantrine)(lumefantrine) 1 - 6 days1 - 6 days

Artemisinin Artemisinin derivativesderivatives

derived from Chinese derived from Chinese plant plant Artemesia annua Artemesia annua

4 - 11 hrs (DHA: 11 - 12 4 - 11 hrs (DHA: 11 - 12 hrs)hrs)

TCN, DCNTCN, DCN Antibiotics + QuinineAntibiotics + Quinine TCN: 8 hrs, DCN 14 - 24 TCN: 8 hrs, DCN 14 - 24 hrshrs

WHO/CDS/RBM/2001.33

White NJ. Antimalarial drug resistance. J of Clin Invest., 2004 ; 113(8): 1084-1092

Pharmacokinetic properties of generally available anti-malarial drugs

In vivoIn vivo pharmacodynamics pharmacodynamics

Antimalarial drugsAntimalarial drugs Estimated PRR Estimated PRR in vivoin vivo

Artemisinin derivativesArtemisinin derivatives 1,000-10,0001,000-10,0004-aminoquinolines, halofantrine4-aminoquinolines, halofantrine 100-1000100-1000Quinine, mefloquine, SPQuinine, mefloquine, SP 10-10010-100Antimalarial antibioticsAntimalarial antibiotics 5 - 105 - 10

PRR = parasite reduction ratio: baseline parasite count/parasite count 48 hours later: this rises if there is background immunity and falls with resistance

White NJ. Antimocrobial Agents and Chemotherapy, 1997; 41 (7): 1413-1422

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).

Parasite stage specific activity varies Parasite stage specific activity varies between compoundsbetween compounds

DHFR inhibitors – narrow window of DHFR inhibitors – narrow window of activity on 2activity on 2ndnd half of parasite life cycle half of parasite life cycle

Quinine, mefloquine – wide time window Quinine, mefloquine – wide time window but only on 2but only on 2ndnd half of life cycle half of life cycle

Chloroquine and halofantrine - wider time Chloroquine and halofantrine - wider time window on circulating formswindow on circulating forms

Artemisinins – broadest range of all, with Artemisinins – broadest range of all, with considerable effect on ring stages and considerable effect on ring stages and early immature gametocyte stageearly immature gametocyte stage

The dose-response curve in malaria. The dose-response curve in malaria.

White NJ. Trends in Parasitology, 2002: 18: 458-464

• Increasing drug resistance leads to a rightward shift in the dose- response Increasing drug resistance leads to a rightward shift in the dose- response or concentration effect relationship. or concentration effect relationship. • The principal effect in uncomplicated malaria is parasite killing.The principal effect in uncomplicated malaria is parasite killing.

Antimalarial Pharmacokinetics and Antimalarial Pharmacokinetics and ResistanceResistance

Drug characteristics thatDrug characteristics that may select for resistance:may select for resistance: Poor oral bioavailability Poor oral bioavailability

with wide range in blood with wide range in blood levelslevels

Drugs with long terminal Drugs with long terminal

elimination half lifeelimination half life

CQ MEFART

White NJ. Antimalarial drug resistance. J of Clin Invest., 2004 ; 113(8): 1084-1092

Philippines

Not available or zero

Incidence of confirmed malaria (per 1000), 2000

0.001 - 0.50.5 - 11 - 55 - 1010 - 2020 - 50

Source: WHO, 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)

Geographical Distribution of Malaria in the Philippines

(Based on 10-year Ave, 1991 -2000)

Source: Malaria Control Program, 2000

GEOGRAPHICAL DISTRIBUTION OF MALARIA CASESGEOGRAPHICAL DISTRIBUTION OF MALARIA CASESPHILIPPINES, 2003PHILIPPINES, 2003

Category A Provinces• 9 provinces• More than 1000 cases

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

Manila

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)

Sequential vs simultaneous treatment with Sequential vs simultaneous treatment with CQ+SP in CQ+SP in P. falciparumP. falciparum malaria in the malaria in the

PhilippinesPhilippines CQ+SP4 : CQ 3 days + SP on Day 4CQ+SP4 : CQ 3 days + SP on Day 4 CQ+SP0 : CQ 3 days + SP on Day 0CQ+SP0 : CQ 3 days + SP on Day 0

CQ+SP4CQ+SP4 CQ+SP0CQ+SP0

Sample size (Sample size (nn)) 1111 21 21Age (yrs)Age (yrs) 2525 32 32Weight (kg)Weight (kg) 6060 52 52Parasitemia (Parasitemia (cummcumm)) 13,284 13,284 18,876 18,876PCT (hrs)PCT (hrs) 4848 39 39FCT (hrs)FCT (hrs) 3434 24 24parasite tparasite t1/21/2 (hrs) (hrs) 5.75.7 2.5 2.5 p=0.006p=0.006

Sequential vs simultaneous treatment with CQ+SP in Pf malaria in Sequential vs simultaneous treatment with CQ+SP in Pf malaria in the Philippines 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 220AUC CQ 2299 day ng/ml AUC CQ 1980 day ng/ml DCQ 1845 DCQ 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 5.7 DCQ 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 5.9 DCQ 8.5 Sulfa 10.9 Pyrim 2.9

Sequential vs simultaneous treatment with CQ+SP in Pf malaria in Sequential vs simultaneous treatment with CQ+SP in Pf malaria in the Philippinesthe Philippines

CQ + SP4 CQ + SP0

PCT (hrs)PCT (hrs) 4848 39 39 FCT (hrs)FCT (hrs) 3434 24 24 parasite t1/2 (hrs)parasite t1/2 (hrs) 5.75.7 2.5 (p=0.006) 2.5 (p=0.006)

Parasite elimination half-life (t1/2): determined by linear regression from its maximumParasite elimination half-life (t1/2): determined by linear regression from its maximumpeak to zero, maybe a better indicator of the rate of complete parasite reductionpeak to zero, maybe a better indicator of the rate of complete parasite reduction

New Malaria Drug PolicyNew Malaria Drug PolicyAO. 129 s. 2002, MCP- DOHAO. 129 s. 2002, MCP- DOH

““Old” Drug PolicyOld” Drug Policy1st line: Chloroquine1st line: Chloroquine2nd line: Sulfadoxine-2nd line: Sulfadoxine-

Pyrimethamine (SP)Pyrimethamine (SP)3rd line: Quinine3rd line: Quinine + Primaquine+ Primaquine

New Drug PolicyNew Drug Policy1st line:1st line: CQ+SPCQ+SP2nd line:2nd line: Artemether + Artemether +

lumefantrine lumefantrine ((Coartem™Coartem™))

3rd line: 3rd line: Quinine + anti- Quinine + anti- biotic (TCN, Doxycyline, biotic (TCN, Doxycyline, Clindamycin)Clindamycin)

+ Primaquine+ Primaquine

CQ+SP and AL (CQ+SP and AL (CoartemCoartem™) efficacy in ™) efficacy in selected study sites, Philippines, 2001-2004selected study sites, Philippines, 2001-2004

Com Val & ADS, 2001 CQ+SP 82% ACPR AL 100% ACPR

On-going TES, 2005

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

ACPR: Adequate Clinical and Parasitological Response

AcknowledgementsAcknowledgementsMalaria Study Group, Research Institute for Tropical Malaria Study Group, Research Institute for Tropical Medicine (RITM), Department of Health, AlabangMedicine (RITM), Department of Health, Alabang

Infectious Disease Office, Department of Health, Infectious Disease Office, Department of Health, Manila Manila

Essential National Health Research, DOHEssential National Health Research, DOH

Partners: French government, Hopital Pitie-Partners: French government, Hopital Pitie-Salpetriere, Paris, France; WHO/RBM, US CDC, Salpetriere, Paris, France; WHO/RBM, US CDC, USAID, US NAMRU2, Global Fund, AusAIDUSAID, US NAMRU2, Global Fund, AusAID

Pharmaceutical IndustriesPharmaceutical Industries

THANK YOU!