Disease : Malaria (Plasmodium falciparum / P. vivax infection)
Category : Infectious Disease — Vector-Borne Parasitic
Date Added : 2026-07-06
Model Abbreviation : mal
11 subgraph clusters · 152 nodes · cross-cluster regulation edges
Malaria is caused by Plasmodium spp. protozoa transmitted by female Anopheles
mosquitoes. P. falciparum causes the great majority of severe disease and death
(cerebral malaria, severe anemia, multi-organ failure) via cytoadherent
sequestration of mature-stage parasites in the microvasculature. P. vivax and
P. ovale form dormant hepatic hypnozoites that cause relapse weeks to
months after apparent cure unless an 8-aminoquinoline radical cure is given.
Artemisinin-based combination therapy (ACT) is first-line treatment worldwide;
emerging partial artemisinin resistance (K13 propeller mutations) threatens
control in the Greater Mekong Subregion and, increasingly, East Africa.
Process
Mechanism
Clinical Consequence
Liver Stage
Sporozoite → hepatocyte → exo-erythrocytic schizogony (6–16d)
Pre-patent period; hypnozoites (P. vivax/ovale) → relapse
Erythrocytic Cycle
48h ring→trophozoite→schizont→rupture (P. falciparum)
Cyclic fever (paroxysm), exponential parasitemia rise
Sequestration
PfEMP1 (var genes) binds ICAM-1/CD36/EPCR/CSA
Cerebral malaria, placental malaria; parasites invisible on smear
Hemolysis
Schizont rupture destroys host RBC + splenic clearance
Severe anemia, blackwater fever (hemoglobinuria)
Cytokine Storm
Hemozoin/GPI-PAMPs → TLR2/9 → TNF-α/IL-6/IL-1β
Fever paroxysm, hypoglycemia, acidosis
Naturally-Acquired Immunity
Repeated exposure → anti-PfEMP1/MSP1/AMA1 antibodies
Premunition (asymptomatic parasitemia) in endemic adults
Antimalarial Drug Classes
Class
Mechanism
Key Drugs
Notable PK
Endoperoxide (artemisinin)
Heme/Fe²⁺-activated free-radical alkylation; broad, dominant ring-stage kill
Artesunate → DHA
t½ ~0.5–1h; PRR ~10⁴/cycle
Aryl-amino alcohol
Heme detoxification inhibition
Lumefantrine, Mefloquine
t½ 3–21 days (post-treatment prophylaxis)
Bisquinoline
Hemozoin formation inhibition
Piperaquine
t½ 20–33 days
4-Aminoquinoline
Heme polymerization inhibition
Amodiaquine → Desethyl-AQ
t½ (DEAQ) ~9–18 days
8-Aminoquinoline
Hypnozoiticidal + gametocytocidal (CYP2D6-dependent)
Primaquine, Tafenoquine
Oxidative hemolysis risk in G6PD deficiency
Recommended WHO-Guideline Regimens
Regimen
Use Case
Advantages
Limitations
Artemether-Lumefantrine (AL)
First-line uncomplicated P.f.
Widely available, well-tolerated
Twice-daily × 3d, food required
Artesunate-Amodiaquine (ASAQ)
First-line (Africa)
Once daily
QT risk, AQ-related neutropenia (rare)
Dihydroartemisinin-Piperaquine (DP)
First-line, longest prophylaxis
Once daily × 3d
QTc prolongation
IV Artesunate
Severe malaria (WHO preferred over quinine)
Superior mortality vs quinine (AQUAMAT/SEAQUAMAT)
Requires ≥24h parenteral therapy then oral ACT
ACT + Primaquine (14d)
P. vivax/ovale radical cure
Prevents relapse
Requires G6PD testing
#
Compartment
Description
Units
1
AS_GUT
Artesunate gut depot
mg
2
AS_PLASMA
Artesunate plasma
mg/L
3
DHA_PLASMA
Dihydroartemisinin (active metabolite)
mg/L
4
LUM_GUT
Lumefantrine gut depot
mg
5
LUM_CENTRAL
Lumefantrine central
mg/L
6
LUM_PERIPH
Lumefantrine peripheral
mg/L
7
PPQ_GUT
Piperaquine gut depot
mg
8
PPQ_CENTRAL
Piperaquine central
mg/L
9
PPQ_PERIPH
Piperaquine peripheral
mg/L
10
AQ_GUT
Amodiaquine gut depot
mg
11
DEAQ_PLASMA
Desethylamodiaquine (active metabolite)
mg/L
12
PQ_GUT
Primaquine gut depot
mg
13
PQ_PLASMA
Primaquine plasma
mg/L
14
RBC_U
Uninfected RBC pool
cells/µL
15
PRBC_RING
Ring-stage infected RBC
parasites/µL
16
PRBC_TROPH
Trophozoite-stage infected RBC
parasites/µL
17
PRBC_SCHIZONT
Schizont-stage infected RBC (sequestered)
parasites/µL
18
LIVER_PARASITE
Liver-stage/hypnozoite burden
arbitrary units
19
GAMETOCYTE
Mature (Stage V) gametocyte density
gametocytes/µL
20
HB
Hemoglobin
g/dL
21
TEMP
Body temperature
°C
22
IMMUNITY
Acquired immunity index
0–1
Core ODE System (age-structured erythrocytic cycle) dRing/dt = new_infections − k_RT·Ring − E_AS·Ring
dTroph/dt = k_RT·Ring − k_TS·Troph − (0.6·E_AS + E_partner)·Troph − gam_commit·k_RT·Ring
dSchizont/dt = k_TS·Troph − k_SR·Schizont − 0.8·E_partner·Schizont
new_infections = (Liver_egress + burst·k_SR·Schizont) · inv_eff0·(1−immune_block·IMMUNITY)
E_drug = Emax · C^h / (EC50_eff^h + C^h) [Hill/Emax]
EC50_AS,eff = EC50_AS · (1 + (Kres_shift−1)·K13_RES) [artemisinin resistance]
dHB/dt = −hb_per_rupture·(k_SR·Schizont) + erythropoietic compensation
dTEMP/dt = (37 + fever_drive(rupture flux) − TEMP) · k_temp_decay
Calibration notes: artesunate/DHA PK from Morris (2011, Malar J ) population PK;
lumefantrine and piperaquine PK from Tarning (2012 CPT ; 2008 AAC ); ring-stage
killing kinetics from Saralamba (2011, PNAS ) and the WWARN Parasite Clearance
Estimator methodology; K13/ring-stage-survival resistance parameterization from
Ashley (2014, NEJM ).
#
Scenario
Regimen
Notes
1
Untreated, non-immune
—
Natural history, traveler/naive host
2
Untreated, semi-immune
—
High baseline immunity (premunition)
3
Artemether-Lumefantrine
AL, 6-dose 3-day
WHO first-line
4
Artesunate-Amodiaquine
ASAQ, 3-day
First-line (Africa)
5
Dihydroartemisinin-Piperaquine
DP, 3-day
Longest post-treatment prophylaxis
6
Severe malaria
IV Artesunate → oral AL
WHO-preferred severe malaria pathway
7
Artemisinin resistance
K13 C580Y + standard AL
Delayed clearance/recrudescence risk
8
P. vivax + radical cure
ACT + 14-day Primaquine
Prevents relapse
9
P. vivax, no radical cure
ACT only
Hypnozoite-driven relapse
Tab
Content
① Patient/Infection Profile
Species, baseline parasitemia/immunity, WHO severe-malaria criteria
② Drug PK
DHA, partner-drug (LUM/PPQ/DEAQ), and primaquine plasma concentrations
③ Parasite Dynamics
Peripheral parasitemia, stage composition, gametocyte carriage
④ Clinical Endpoints
Parasite/fever clearance time, Day-28 ACPR outcome
⑤ Scenario Comparison
Multi-regimen parasitemia clearance comparison
⑥ Biomarkers
Hemoglobin, temperature, immunity index, liver/hypnozoite burden
⑦ Resistance (K13)
Wild-type vs K13-mutant clearance kinetics
Key Clinical Trial Evidence
Trial
Regimen
n
Key Finding
SEAQUAMAT (2005)
IV Artesunate vs Quinine (Asia, severe malaria)
1461
Mortality 15% vs 22% (RRR 34.7%)
AQUAMAT (2010)
IV Artesunate vs Quinine (Africa, pediatric severe malaria)
5425
Mortality 8.5% vs 10.9% (RRR 22.5%)
Ashley et al. (2014, TRAC)
K13 genotype vs parasite clearance half-life
1241
K13 mutations → delayed clearance across GMS
WWARN DP pooled analysis
DHA-piperaquine efficacy
>7000
Day-42 PCR-adjusted efficacy >95% (most sites)
CDC/WHO Radical Cure guidance
Primaquine/Tafenoquine + G6PD testing
—
Point-of-care G6PD testing recommended before radical cure
File
Description
mal_qsp_model.dotGraphviz DOT mechanistic map source (11 clusters, 152 nodes)
mal_qsp_model.svgSVG rendered mechanistic map
mal_qsp_model.pngPNG rendered mechanistic map (150 dpi)
mal_mrgsolve_model.Rmrgsolve ODE model (22 CMT, 9 scenarios)
mal_shiny_app.RShiny dashboard (7 tabs, interactive PK/PD simulation)
mal_references.mdPubMed references (10 sections)
README.mdThis file
