atovaquone-proguanil
Brand: Malarone
Prototype Drug
Drug Class: combination antimalarial
Drug Family: antiparasitic
Subclass: mitochondrial complex III inhibitor + antifolate combination
Organ Systems: infectious-disease
Mechanism of Action
Atovaquone inhibits the mitochondrial electron transport chain at cytochrome bc1 complex, collapsing the mitochondrial membrane potential; cycloguanil (active metabolite of proguanil) inhibits dihydrofolate reductase; combination is synergistic and active against both liver and blood stages.
mitochondrial cytochrome bc1 complex III (atovaquone)dihydrofolate reductase (cycloguanil, proguanil metabolite)
Indications
- malaria prophylaxis for travelers to chloroquine-resistant regions
- malaria treatment (P. falciparum including chloroquine-resistant)
Contraindications
- atovaquone/proguanil hypersensitivity
- severe renal impairment (CrCl <30 mL/min — use alternative for prophylaxis)
- pregnancy (insufficient data)
Adverse Effects
Common
- GI upset
- headache
- abdominal pain
Serious
- hepatitis (rare)
- Stevens-Johnson syndrome (rare)
- neutropenia (rare)
Pharmacokinetics (ADME)
| Absorption | atovaquone: 40% bioavailability fasting, significantly increased (2.5–3x) with fatty food; proguanil: ~55% bioavailability; administer with food or milky drink |
| Distribution | atovaquone: large Vd, highly lipophilic; proguanil/cycloguanil: moderate distribution |
| Metabolism | atovaquone: minimal; proguanil metabolized by CYP2C19 to active cycloguanil |
| Excretion | atovaquone: fecal (>94% unchanged); proguanil/cycloguanil: renal |
| Half-life | atovaquone 2–3 days; proguanil 12–21 hours |
| Onset | rapid |
| Peak | 2–4 hours |
| Duration | once-daily dosing |
| Protein Binding | atovaquone 99%; proguanil 75% |
| Vd | large (atovaquone) |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| rifampin | reduces atovaquone levels by ~50%; avoid combination | major |
| warfarin | atovaquone may enhance anticoagulant effect; monitor INR | moderate |
| metoclopramide | reduces atovaquone absorption; avoid combination | moderate |
Nursing Considerations
- Must be taken with food or milky drink — atovaquone absorption is critically dependent on fat content.
- For prophylaxis: start 1–2 days before travel and continue for 7 days after return (shorter post-travel course than chloroquine or mefloquine).
- Advise patients to take at the same time each day; if vomiting occurs within 1 hour of dose, repeat the dose.
- Atovaquone-proguanil is NOT effective for P. vivax hypnozoites; primaquine or tafenoquine must be added if P. vivax exposure is possible.
Clinical Pearls
- Atovaquone-proguanil is one of three recommended options for malaria chemoprophylaxis in chloroquine-resistant areas (along with mefloquine and doxycycline); its advantages include once-daily dosing, minimal neuropsychiatric side effects compared to mefloquine, and only 7 days post-travel continuation.
- CYP2C19 poor metabolizers produce less cycloguanil from proguanil, theoretically reducing antifolate efficacy; however, atovaquone alone provides substantial antimalarial activity, and clinical failures attributable solely to CYP2C19 status are uncommon.
Safety Profile
Pregnancy use-with-caution
Lactation use-with-caution
Renal Adjustment Required
Hepatic Adjustment Not required
TDM Not required
Concordance Terms
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